Decoding ALS: from genes to mechanism

Abstract

Preface Amyotrophic lateral sclerosis (ALS) is a progressive and uniformly fatal neurodegenerative disease. A plethora of genetic factors underlying ALS have now been identified that drive motor neuron degeneration, increase susceptibility to the disease, or influence the rate of progression. Emerging themes include dysfunction in RNA metabolism and protein homeostasis, with specific defects in nucleocytoplasmic trafficking, induction of endoplasmic reticulum stress, and impaired dynamics of ribonucleoprotein bodies such as RNA granules that assemble through the process of liquid-liquid phase separation. Extraordinary recent progress in understanding the biology of ALS provides new grounds for optimism that meaningful therapies for ALS will be identified.

Tau protein liquid–liquid phase separation can initiate tau aggregation

“…A similar transition can lead to aberrant stress granule dynamics of C9orf72‐derived dipeptide repeats, which plays a role in the pathogenesis in amyotrophic sclerosis (ALS; Taylor et al , 2016). In different neurodegenerative diseases such as AD and FTD, hyperphosphorylated tau is found in pathological tau aggregates (Gong et al , 2005), and the phosphorylation pattern of p‐tau441 has been shown to be similar to that found in tau aggregates from AD brains (Mair et al , 2016).…”

CNS inflammation and neurodegeneration

“…Motor neuron death in ALS often occurs in association with protein inclusions. Familial ALS accounts for 10% of cases and has been associated with mutations in the SOD1 gene and ubiquitin-related genes (155). Glutamate levels are elevated in ALS patient cerebrospinal fluid, possibly because of aberrant expression of the astrocytic glutamate transporter EAAT2 (156).…”

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

“…Dipeptide repeat protein accumulations and/or RNA inclusions have been shown to impair nucleocytoplasmic transport in affected cells (100-102); however, ongoing studies are needed to determine the connection between nucleocytoplasmic transport defects and selective neuronal death in ALS/FTD. Potential gain-of-function mechanisms were recently reviewed elsewhere (103,104). surveillance cells of the brain and are highly sensitive to changes in their environment.…”