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Basic Research

Basic Research

ALS basic research deals with the aetiology and pathogenesis of the diseases, comprising motor neuron biology and related areas (e.g. cell death pathways, protein misfolding, immune response, mitochondrial function, cell signalling circuitries), as well as research directly related to ALS (excitotoxicity, non-neuronal cells involvement, development of cell and animal models, genetics of fALS and sALS).

Despite years long efforts and some important insights into the mechanisms underlying the disease pathogenesis, ALS research has not yet made the disease easier to understand, and, even less, to manage. Basic science ALS research today integrates studying diverse pathological aspects at the molecular or cellular level using test tubes, cell cultures and animal models that mimic disease in humans. These studies do not necessarily produce results that are immediately relevant for ALS patients medical care, but the knowledge gained is essential for understanding the cellular and molecular changes that trigger the disease providing thus information on possible diagnostic and therapeutic strategies.

The current research focuses on several main research areas  and  a development of cellular and animal models of a disease. Ever more frequently this includes integrated research projects conducted at European and national level.

Disease risk /causative factors

ALS genetics

Similarly to other neurodegenerative diseases like Alzheimer's Disease (AD), Parkinson's Disease (PD) or prion disease, ALS occurs predominantly in a sporadic manner (sALS), although several mutations have been identified as causative in rare cases of familial disease (fALS) that account for 5-10% of all cases.

At present, eight genes with proved fALS causation have been described and at least eight other loci have been mapped (Leigh 2009). Most of these are identified via genetic linkage analysis in affected families and display an autosomal dominant inheritance pattern with some autosomal recessive pedigrees reported. In different populations 12-23% of fALS patients show mutations in Cu-Zn superoxide dismutase (SOD1) gene. Since 1993, over 140 mutations have been found in the SOD1 gene with five different modes of inheritance. Mutations in Alsin (ALS2), Dynactin (DCTN1), senataxin (SETX), Angiogenin (ANG) and VAMP/synaptobrevin-associated membrane protein B (VAPB) appear to be very rare and analysed only in a scientific settings. Finally, two structurally and functionally related genes coding for TAR DNA binding protein (TARDP) and fused in sarcoma/translated in liposarcoma (FUS/TLS), have recently been linked to ALS. Overall 30 TARDP mutations and 13 FUS mutations were detected in 1-3% and 2-5% fALS patients, respectively.

SOD1 mutations in ALS

In different populations 12-23% of patients diagnosed with fALS and 2-7% of sALS patients carry a SOD1 mutation. Since 1993, 139 mutations have been found in the SOD1 gene on chromosome 21 with five different modes of inheritance. Noteworthy, some SOD1 mutations with determinate inheritance and penetrance pattern are related to a characteristic disease phenotype. E.g. the most frequent SOD1 mutation is the D90A often inherited as recessive and determining slow disease progression. Some other mutations (l113T, G93S, D76Y) are instead correlated to a diminished disease penetrance.

Rather than impairment of its antioxidant function, mutations in the SOD1 gene are likely to cause disease through a toxic gain of function-possibly an increase in the propensity of the protein to misfold and to aggregate. It has been demonstrated that SOD1 mutations only in motor neurons are sufficient to induce ALS like syndrome in mice albeit the presence of mutations in surrounding astrocytes is shown to accelerate and exacerbate the disease.

SOD1 transgenic cell lines and transgenic mice have been employed as laboratory models to study molecular mechanisms of neurodegeneration in ALS and evaluate the efficacy of potential therapeutic compounds and approaches in  preclinical settings.

SOD1 toxic mutant protein is considered as a possible molecular target in ALS therapy. Specific therapeutic systems are under evaluation (gene/ RNAi therapy, SOD1 directed antibodies) to prevent synthesis or inactivate citotoxic SOD1 mutant protein. In this perspective, finding an ALS patient to be a carrier of a SOD1 mutation might turn out to be advantage. Moreover, development of DNA-SOD1 tests could provide important diagnostic and prognostic information for a distinct fraction of ALS patients.

TARDBP mutations in ALS

Seventeen mutations in the TARDBP gene on chromosome 1, which encodes the TAR DNA binding protein (TDP-43), have been described in individuals with familial and sporadic amyotrophic lateral sclerosis. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative.

TARDBP mutations account for 2-5% of fALS cases. TDP-43 is a major component of the ubiquitinated inclusions that characterise over 90% of sALS cases. In contrast, the absence of pathological TDP-43 in cases with SOD1 mutations implies that motor neuron degeneration in these cases may result from a different mechanism, and that cases with SOD1 mutations may not be the familial counterpart of sporadic ALS.

FUS/TLS mutations in ALS

13 mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene on chromosome 16 have been reported specific for familial ALS. The FUS/TLS protein binds to RNA, functions in diverse processes, and is normally located predominantly in the nucleus. In contrast, the mutant forms of FUS/TLS accumulated in the cytoplasm of neurons, a pathology that is similar to that of the gene TAR DNA-binding protein 43 (TDP43), whose mutations also cause ALS. Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders.

ALS2 mutations in ALS

Autosomal recessive mutations in the alsin (ALS2) gene linked to chromosome 2q33 have been linked to juvenile-onset amyotrophic lateral sclerosis (ALS2), primary lateral sclerosis and juvenile-onset ascending hereditary spastic paraplegia. To date, at least 12 different mutations in the 34 exons of the ALS2 gene have been described in African and Asian families with juvenile ALS and PLS, and in European and Asian families with HSP Except for two recently identified missense mutations, all other mutations in the ALS2 gene lead to a premature stop codon and likely to result in protein instability and loss of function the encoded protein alsin. The physiological role of alsin is still unclear.

DCTN1 mutations in ALS

Missense mutations in DCTN1 gene encoding the p150Glued subunit of dynactin have been linked to both familial and sporadic ALS.  Dynactin p150Glued is a critical component of a multiprotein complex with dynein, the molecular motor that plays critical role in intracellular and axonal transport. This complex is required for fast retrograde transport of vesicles, organelles, RNAs and proteins along microtubules. Impaired dynein/dynactin function can explain several pathological features observed in ALS patients and is shown to induce motor neuron disease in mice characterized by defects in vesicular transport in cell bodies of motor neurons, axonal swelling and axo-terminal degeneration and autophagic cell death. Recent evidence indicate that dynactine mutations may be beneficial in some forms of ALS.

SETX mutations in ALS

Three missense mutations have been described in the senataxin gene (SETX) that encodes a novel DNA/RNA helicase in three unrelated families with ALS4, a rare, childhood- or adolescent-onset, slowly progressive form of ALS. Although its function remains unknown, SETX contains a DNA/RNA helicase domain with strong homology to human RENT1 and IGHMBP2, two genes encoding proteins known to have roles in RNA processing. These observations of ALS4 suggest that mutations in SETX may cause neuronal degeneration through dysfunction of the helicase activity or other steps in RNA processing.

VAPB mutations in ALS

Missense mutation (P56S) in the VAMP/synaptobrevin-associated membrane protein B (VAPB) gene was correlated with late onset slowly progressive ALS (ALS8) in several large Brasilian families. This gene encodes a  vesicle trafficking protein and are likely to to disrupt intracellular membrane transport and secretion. Moreover, VAPB is physiologically involved in unfolded protein response (UPR) suggesting that the P56S mutation may contribute to the motor neuronal degeneration  by impairment of VAPB  to mediate UPR. In any case VAPB muattions are rare and do not seem to be related to sALS.

VEGF and ANG mutations in ALS

Although no mutations in the vascular endothelial growth factor (VEGF) have been associated with ALS,  sequence alterations in the promoter region of the (VEGF) gene have been implicated in increasing the risk of developing ALS.  Abolishing the hypoxia promoter on the VEGF gene induces ALS-like disease in mice; on the contrary, deliver VEGF to motor neurons by viral vectors  delay onset of disease and increase lifespan in SOD1 mutant mice. Besides VEGF, angiogenin is the second so-called angiogenic factor implicated in ALS. Heterozygous missense mutations in the coding region of angiogenin (ANG), have been recently reported in both fALS and sALS patients associated with functional loss of ANG activity. Angiogenin is a ribonuclease with potent angiogenic activity. It role in motor neuron physiology and the functional consequences of mutations are unknown. In any case, ALS linked ANG mutations are rare and seem restricted to Irish and Scottish populations. Importantly, ANG is the first gene whose loss-of-function mutations are associated with ALS pathogenesis.

Sporadic ALS

At present, the role of genetic factors in determination of a sporadic disease is not clear. It has been suggested that some of the fALS-linked genes might also be involved in the pathology of sporadic forms of the disease as shown in other neurodegenerative diseases (i.e.α-synuclein in PD). Although some of familial mutations in SOD1, FUS and DCTN1 have been reported in a small portion of sporadic ALS cases, it is possible that these are either de novo or low penetrance mutations (ref). TARDP mutations instead have been associated to both fALS and sALS and in similar proportions (1-3%). Such a low gene mutation rate is, however, in a discrepancy with a high prevalence of TDP-43 proteinopathy in sALS patients (> 90%). In addition, most of the genes that are proposed to act as risk factors for sporadic disease came up from the findings in limited populations, while resulting not significant in studies performed on large cohorts of patients drawn from other geographic areas. These include angiogenin in Irish and Scotish population (Greenway 2004), VEGF in Swedish and Belgium cohorts or DCTN1 in a German study (Munch C 2004). Others are described as private mutations in a very few sALS patients (NFH, EAAT2 , NAIP, peripherin, HFE, PON1, PON2 and SPG4 genes).

Reports on novel ALS related mutations constantly extend the list of genes that might be implicated in a disease although most of them are still awaiting for the conclusive studies that prove the associations emerged from genetic screenings.  Latest example is optineurin (OPTN), some mutations of which are suggested to cause familial ALS . Noteworthy, optineurin staining appears to accumulate in both sporadic and familial ALS cases without any OPTN mutations. Furthermore, optineurin colocalization with both SOD1 and TDP-43 in inclusions present in many ALS samples. This, together with its role in intracellular transport and RNA metabolism, two cellular activities linked to ALS, might indicate otineurin as another common component of ALS pathology.

Two recent Italian led studies proposed novel candidates for fALS causative genes. First implicate mutations in spatacsin, gene known to cause autosomal recessive hereditary spastic paraplegia, in pathogenesis of autosomal recessive juvenile ALS. The second study correlates specific mutations in PON genes, coding for paraoxonases, enzymes  with anti-oxidant properties and a role  in organophosphate metabolism, to some forms of familial ALS. Thus mutations in these genes, found also in individuals with sporadic ALS, might provide a genetic predisposition to neuronal degeneration caused by  aging and exposure to environmental toxins. 

Environmental factors

Despite the discovery of several genes responsible for familial forms of ALS, the vast majority (~ 90%) of the cases occurs as sporadic forms, likely resulting from complex interplay between genetic predisposition and environmental exposures. All reported associations of environmental risk factors with ALS are based on clinical and epidemiologic observations. Results of the conducted studies are often inconclusive being conflicting or not repeated. Currently no robust evidence or conclusive proof exists for any environmental factor as a causative or risk factor for sporadic ALS. Environmental factors that have been studied in relation to the increased disease risk or even with protection, include:

- Occupational exposure to pesticides, metals, neurotoxins and electromagnetic fields; Several studies report an increased risk of developing ALS among individuals occupationally exposed to lead, agricultural chemicals or electromagnetic fields. An increased incidence of ALS among war veterans, especially those from the first Gulf War suggests an exposure to neurotoxins as possible risk factor. other occupational risk factors for ALS include radiation, electrical shocks, work with welding or soldering materials, employment in paint, petroleum or dairy industries.

Physical activity and related traumas; The observation of increased frequency of ALS  in some athletes categories such as in Italian professional soccer players and National Football League players in USA, has led to the assessment of physical activity as a risk factor for the disease. This argument has been extensively debated and studied with no universal agreement achieved. Several hypothesis have been formulated in order to explain the causative agent of ALS among soccer players, including also drugs and doping, dietary supplements, pesticides used on the playgrounds, head and spinal cord trauma history. Notably, recent evidence support the hypothesis that repeated head injury might increase ALS risk.

- Lifestyles and dietary habits; Geographic clustering of ALS in Chamorro Indians of Guam and Marianas Island has been a focus of intense research interest for over half a century. Epidemiological studies have indicated dietary habits as the only variable significantly associated with the Amyotrophic Lateral Sclerosis-Parkinsonism-Dementia Complex (ALS/PDC) incidence in Guam. Subsequently, a naturally occurring toxin - a non-protein amino acid beta-N-methylamino-l-alanine (BMAA) produced by Cyanobacteria, was isolated from cycads seeds and cycades-derived flour, and identified as potential risk/causative ALS factor. Moreover, Chamorro Indians get exposed to very high concentration of BMAA by a consumption of flying foxes that themselves feed on cycades. Noteworthy, increased ALS incidence is registered also in the native populations on Kii peninsula of Honsshu Island in Japan and Auyu and Jakai of south west New Guinea, other two areas where the cycad seeds are used either dietarily or medically. With a purified L-isomer of BMAA, Spencer et al. produced an illness in monkeys with features of human ALS and possible Parkinson's disease. Moreover, there is evidence from recent studies on ALS and AD patients in Canada and the USA that BMAA may be involved in the neurodegenerative process of at least some sporadic cases of these disorders.

Recent studies have reported the potential significance of a certain high caloric dietary intake in the prevention of ALS. In particular ketogenic diet was shown to slow the progression of the clinical and biological manifestations of ALS in a mouse model.

Of other lifestyle related factors (years of education, drugs and alcohol consumption, rural residence etc.) only cigarette smoking appeared to be independently associated to the occurrence of sALS.

- Viruses; Viral etiology of ALS is a recurring idea that researchers have been debating for decades. Selective vulnerability of motor neurons to certain viruses such as Polio virus, some entero- and retroviruses have been described.  It is known that retroviral infections may cause motor neuron damage and ALS-like syndromes in both laboratory animals and humans. Some epidemiological and experimental data suggest a pathogenetic link between HIV infection and ALS. Noteworthy patients with HIV-associated ALS syndrome displayed significant reversal of neurological symptoms after the antiretroviral therapy. However, although evidence exists that correlate viral infections to some forms of ALS, as of yet no causal relationship has been proved.

- Race/ethnicity; ALS is one of the most common neuromuscular diseases worldwide, and people of all races and ethnic backgrounds are affected. Most population based studies that have revealed an uniform disease incidence across Caucasian populations have been conducted in Europe and North America, and have captured mainly the white individuals of European origin. Although apparently lower ALS incidence in non European countries as well as in African Americans and Hispanic populations may be confounded by reduced ascertainment, there is evolving evidence that differences in ALS incidence and prevalence may exist across different ethnicities.

- Gender differences; All epidemiologic surveys of ALS report consistently a male preponderance of  approximately 1.5 to 1 that concerns all forms of sporadic ALS. Curiously, male predisposition has been observed also in other neurodegenerative syndromes such as parkinsonism and dementia. Besides incidence of ALS, gender might be one of the factors that influence the expression of the disease at least in some forms of ALS. The age related frequency of ALS suggests the possible role of hormones as disease modifiers - the testosterone depletion with age in men and menopause in women seem to have an opposite effect on the risk of ALS occurrence. Estrogens are supposed to have a protective role as free radical scavengers, anti-apoptotic agents or by affecting cytokine production, or binding intracellular receptors that act as transcription factors to regulate expression of specific genes. evidence for protective influences in women is accumulating from observations in some familial ALS forms where females have been shown to have later onset and slower progression with respect to men bearing the same mutation. On the other hand, the androgenic inhibition of some protective mechanisms, such as a heat shock response, involved in rescuing of degenerating neurons, has been reported recently. Finally, the increased incidence of ALS in males was recently associated to their increased susceptibility to the development of vascular diseases with respect to premenopausal females, in view of suggested role of angiogenic factors such as VEGF and angiogenin in motor neuron pathology.

- Early life exposures and/or epigenetic factors;  Several studies have suggested that maternal age at delivery and exposure to siblings or severe stress of parental bereavement may predispose to ALS. Some of the environmental factors might be involved in neurodegeneration by causing epigenetic modifications and thus interfering with gene regulation in a long-term fashion with pathological results that become obvious later in life. In particular, the emerging correlation between oxidative stress and epigenetic mechanisms might offer new insights into neurodegenerative diseases such as PD, AD and ALS.

- Family history of non-ALS neurodegenerative disease; ALS has some overlapping clinical symptoms and common pathological hallmarks (such as intraneuronal protein aggregations) with other neurodegenerative diseases characterized by selective vulnerability of specific group of neurons, such as  Parkinson's disease, Alzheimer's disease and different forms of dementia.  Evidence exist for a shared genetic susceptibility for degeneration of the motor system (ALS), the cortical areas with cognitive functions (dementia) and the subcortical nuclei involved in motor control (parkinsonism). The cases have been reported of familial co-occurrence of ALS, dementia or parkinsonism. Importantly, in such families, these neurodegenerative diseases occurred randomly with a phenotypic variability consistent with that reported in fALS.

Disease pathophysiology

Mitochondrial disfunction; Mitochondria are cellular fueling pumps implicated in such neurodegenerative diseases as Parkinson's and Alzheimer's. Morphological and biochemical mitochondrial abnormalities have been reported in sALS patients, SOD1 mice and cellular models. In addition, mitochondrial mutations have been described in ALS patients. In ALS patients mitochondria show elevated Ca levels along with trafficking perturbations and nitrative stress. Despite the fact that mitochondria play a central role, both as a target and a trigger, in excitotoxicity, oxidative stress, axonal transport and apoptosis, the intimate underlying mechanism linking mitochondrial defects to motor neuron degeneration in ALS still remains elusive. Recent studies in SOD1 mutant mice postulate that the mislocalization in mitochondria of mutant forms of the protein may account for the toxic gain of function of the enzyme. Finally, activation of the mitochondrial apoptotic pathway is a characteristic feature of mutant SOD1-mediated motor neuron death.

These organelles are especially critical to the motor neurons that die in ALS, as these cells must meet extraordinary energetic demands. However, mitochondrial dysfunction in ALS does not seem to be restricted only to motor neurons as it is also present in other tissues, particularly the skeletal muscle. The presence of this 'systemic' defect in energy metabolism associated with the disease is supported in skeletal muscle tissue by decreased activity of respiratory chain complexes I and IV indicating defective energy metabolism. In addition, the lifespan of transgenic mutant SOD1 mice is increased by a highly energetic diet compensating both the metabolic defect and the motorneuronal function.

Oxidative stress

Oxidative stress and accumulation of reactive oxygen species is known to cause cell death. The increase of oxidative damage with age fits with middle- or advanced age onset of ALS although the age related disease pattern suggests that ALS occurs within a succeptible group within the population rather than veing a disease of aging (Logroscino G J Neurol Neurosurg Psychiatry 2009). Tissue samples from ALS patients show evidence of abnormal free radicals metabolism and cells cultured from ALS patients show increased sensitivity to oxidative damage. Oxidative stress might link with other proposed pathogenic mechanisms such as excitotoxicity and axonal transport defects. Increased intracellular Ca levels as a consequence of excitotoxicity leads to increased formation of NO that in turn reacts with superoxide anions and causes oxidative damage. Also nitration of neurofilament proteins can alter their function and organization and impair axonal transport.

Impaired axonal transport

Active transport along the extensive axons (up to one metre) of motor neurons conveys newly made materials to even the farthest reaching nerve endings, and needed nutrients back to the cell body. SOD1 mice model shows evidence of axonal degeneration and slowed both anterograde and retrograde transport. 

Mutations in related genes are known to cause MND such as HSP and Charcot disease. In ALS rare mutations motor protein dynein and its activator dynactin have been reported. 

Moreover, axonal inclusions have been reported in motor neurons of ALS patients containing neurofilament aggregates. Neurofilaments are key proteins  to defining and maintaining the structure of the axon; disruptions in the neurofilaments can induce these proteins to accumulate, and this can damage the motor neurons to produce symptoms bearing many similarities to ALS. For example, peripherin and α-internexin are two intermediate filament proteins that colocalize with neurofilaments and are found in axonal inclusions in ALS; their overexpression in transgenic mice causes motor neuron degeneration.

Protein misfolding and aggregation

Intra cytoplasmatic inlusions are hallmarks of ALS. The role of protein aggregation in ALS pathogenesis is unclear - they might cause cell toxicity, be only by-products of the neurodegeneration or even a mean of cell protection by sequestering toxic proteins. Ubiquitine positive inclusions are common feature of a number of neurodegenerative diseases.

The mechanisms of protein aggregation include ER stress (unfolded protein response, UPR) and impairment of proteosome system. Increased toxic protein clearance rapresents  possible therapeutic strategy. It has been demonstrated that subtype-selective endoplasmic reticulum (ER) stress responses influence disease manifestations.

TDP-43 was recently identified as the major protein of ubiquitinated inclusions in 95% of ALS cases. Recent identification of TDP-43 mutations in sALS and fALS cases strongly suggests its role in neurodegeneration and prompts the research focus on so-called TDP-43 proteinopathies. 


Refers to a neuronal injury induced by prolonged and excessive excitation, typically by glutamate acting on postsynaptic  NMDA and AMPA receptors. Glutamate's toxicity is apparently due to calcium flooding, leading to increased nitric oxid and free radicals formation, and triggering programmed cell death.

Glutamate CSF levels may be elevated in ALS patients. This elevation has been attributed to the loss of glial glutamate clearing transporter EAAT2. It is stil not clear how EAAT2 disruption occurs given the absence of evidence of mutations, altered expression or splicing in ALS patients. Notably these transporters are particularly susceptible to oxidative modifications.

Increased glutamate clearance has been considered a possible therapeutic approach. Indeed, the only approved ALS drug is Riluzole that is thought to act by inhibiting glutamate release and increasing the extracellular glutamate uptake.

Overall, abnormal glutamate metabolism and loss of glutamate transporters in ALS patients,  along with proved motor neuron susceptibility to glutamate toxicity and clinical efficacy of anti glutamate agents support the role of glutamate excitotoxicity in ALS.


The autoimmune pathogenesis of ALS has long been considered but the evidence to support a conventional autoimmune process has remained inconclusive. In a animal model, induced autoimmune destruction and loss of motorneurons resulted in syndromes closely resambling to human ALS (Smith RG Brain Res Bull 1993). IgG from ALS patients were reported to passively transfer physiological changes characteristic of  ALS at the neuromuscular junction in mice.  It has  been proposed that these "ALS antibodies" interact with and alter the function of calcium channels and that motorneuron may be selectively vulnerable due to their deficient calcim buffering capacity.

The inflammatory process due to an activation of non-neuronal cells, namely microglia, astrocytes and dendritic cells is observed in ALS patients and SOD1 mice, along with  alteration in expression and/or activation of immune molecules. Observed changes involve the innate and adaptive immune responses, the former mediated by  the activation of resident macrophages and microglia, the latter through the infiltration of T lymphocytes and dendritic cells which could secrete cytokines.

It is not clear whether the inflammation that accompanies the death of motor neurons in ALS is a reaction to the death of the cells, or its instigator. Microglial activation occurs at presymptomatic stage inmSOD1 mouse model and is sustained throughout the course of the disease. Activated microglia release mediators that cause astrocytes to downregulate the production of neurotrophic factors and, in turn, secrete additional inflammatory moleculs that further activate microglia closing, thus, a vicious circle. In addition, there is evidence of a linkbetween excitotoxicity and increased levels of some key inflamationmeditors suchas COX-2 that are found in ALS patients and mouse models.

Immunomodulatory therapies have been envisaged for ALS; clinical trials of neuroprotective agents, including stem cells  and non neuronal cells directed approaches are ongoing.

Insufficient neurotrophic/growth factors signaling

Neurons development and maintainment is dependent on crucial trophic factors supply. Decreased levels of neutrophic factors is observed in ALS patients tissues post-mortem and in cell models.

It was proposed that boosting the supply of neurotrophic molecules could help sick neurons back to health. Scientists have gathered direct evidence that trophic factors can salvage dying neurons in animal models of ALS. But human trials have failed so far to follow up on that success.

The mutations in VEFG have been reported as causative of MND in mice, as well as abberant signalling pathways (retinoic signaling i.e.). In some populations mutations in VEGF and angiogenin are indicated as risk factors in sALS. These angiogenic factors are thought to influence motor neurons via direct neurotrophic effect and via their action to maintain blood flow to these highly metabolically active cells. The reduced vascular perfusion that occurs with age, the increased incidence of ALS in males who are more likely to develop vascular disease compared to premenopausal femails, and smoking as risk factor for ALS, provide circumstantial evidence that supports this mechanism.


The final process of MN death in ALS closely resembles a programmed cell death pathway. Key elements of normal apoptotic pathway  are found involved in MN death, including caspases 1 and 9, Bcl2 proteins and apoptosis inhibitors (IAPs). Putative MN specific cell death pathway(s) has been suggested.

As a common feature of ALS, apoptosis represents ideal therapeutic target. Indeed, in mSOD1 mice, broad- spectrum caspase inhibitors, as well as increased expression of Bcl-2 and some apoptosis inhibitors, are shown to slow down the disease progression and extend survival.

The role of non neuronal cells

A growing body of evidence suggests a non-cell autonomous mechanism in ALS pathogenesis as well as in motor neuron protection. Despite somewhat controversial findings from independent studies, it has been suggested that dysfunction localized solely to neurons might not be sufficient for a  disease development, whereas an increasing burden of dysfunction in multiple neuromuscular cell types gives rise to full clinical phenotype. Multiple independent murine studies based on the cell/tissue restricted gene expression or deletion of (trans)genes have reported that isolated expression of mSOD1 in motor neurons is insufficient to initiate motor neuron toxicity. Defective  non-neuronal cells in the local microenvironment is required to fully recapitulate disease symptomatology in murine models whereas functional non-neuronal cells could play a protective role in halting disease propagation. Likewise, therapeutic manipulation within neurons alone only forestalls degeneration while surrounding cells, notably astrocytes and microglia, appears capable of modifying disease progression.

Glial cells that normally support the neuronal function outnumber motor neurones in the brain by five to ten times. When the function of the brain is imbalanced, the glial cells move from a resting state to an activated state and can either preserve neurons from damage or contribute to their de generation and death.  In normal conditions astrocytes provide nutrients for neurones and also ensure the efficient and correct cell-cell interactions.  Microglial cells instead perform a pivotal role in the CNS as the chief mediator of immune function. The role of both cell types in ALS  development is not yet very well understood. Prevailing hypotheses for astrocyte contribution include direct or indirect contributions to glutamate-induced excitotoxicity, impaired metabolic support, alterations in glio-transmission, or direct release of diffusible neurotoxic factors. Numerous studies have also demonstrated microglial activation in the brain and spinal cord of postmortem patients with ALS as well as the presence of elevated cytokines in murine SOD1 models and in the CSF of ALS patients.

Overall, it is likely that glial cells do not trigger the neural degeneration and have little effect on the early disease phase, but have a striking impact on later disease progression.

Besides, ALS pathogenesis includes systemic defects such as muscle hypermetabolism, energy deficit, and widespread alterations of lipid metabolism that were shown to participate in motor neuron degeneration. Current research should now focus on understanding the relationships between these pathological hallmarks and how such global defects lead to the ALS-linked selective loss of motor neurons.

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