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

Decoding ALS: from genes to mechanism

http://dosequis.colorado.edu/Courses/BrainWeb/papers/ALS1.pdf

Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis.

Considerable progress has been made in unraveling the genetic etiology of amyotrophic lateral sclerosis (ALS), the most common form of adult-onset motor neuron disease and the third most common neurodegenerative disease overall. Here we review genes implicated in the pathogenesis of motor neuron degeneration and how this new information is changing the way we think about this fatal disorder. Specifically, we summarize current literature of the major genes underlying ALS, SOD1, TARDBP, FUS, OPTN, VCP, UBQLN2, C9ORF72 and PFN1, and evaluate the information being gleaned from genome-wide association studies. We also outline emerging themes in ALS research, such as next-generation sequencing approaches to identify de novo mutations, the genetic convergence of familial and sporadic ALS, the proposed oligogenic basis for the disease, and how each new genetic discovery is broadening the phenotype associated with the clinical entity we know as ALS.

/pdf/state-of-play-in-amyotrophic-lateral-sclerosis-genetics-2ucxeipw8b.pdf

State of play in amyotrophic lateral sclerosis genetics.

Several recent breakthroughs have provided notable insights into the pathogenesis of amyotrophic lateral sclerosis (ALS), with some even shifting our thinking about this neurodegenerative disease and raising the question as to whether this disorder is a proteinopathy, a ribonucleopathy or both. In addition, these breakthroughs have revealed mechanistic links between ALS and frontotemporal dementia, as well as between ALS and other neurodegenerative diseases, such as the cerebellar atrophies, myotonic dystrophy and inclusion body myositis. Here, we summarize the new findings in ALS research, discuss what they have taught us about this disease and examine issues that are still outstanding.

/pdf/the-changing-scene-of-amyotrophic-lateral-sclerosis-1q1nhg9wa2.pdf

The changing scene of amyotrophic lateral sclerosis

Complex and intricate RNA splicing mechanisms are crucial for gene regulation and for maximizing proteomic diversity. This Review discusses how alterations to splicing mechanisms — such as mutations in pre-mRNAs, or mutations and dysregulation of core spliceosome proteins and other RNA-binding proteins — results in diverse molecular consequences and various diseases. Opportunities for therapeutic correction of these defects are also explored.

/pdf/rna-mis-splicing-in-disease-i60fslhrxv.pdf

RNA mis-splicing in disease

FUS/TLS (fused in sarcoma/translocated in liposarcoma) and TDP-43 are integrally involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We found that FUS/TLS binds to RNAs from >5,500 genes in mouse and human brain, primarily through a GUGGU-binding motif. We identified a sawtooth-like binding pattern, consistent with co-transcriptional deposition of FUS/TLS. Depletion of FUS/TLS from the adult nervous system altered the levels or splicing of >950 mRNAs, most of which are distinct from RNAs dependent on TDP-43. Abundance of only 45 RNAs was reduced after depletion of either TDP-43 or FUS/TLS from mouse brain, but among these were mRNAs that were transcribed from genes with exceptionally long introns and that encode proteins that are essential for neuronal integrity. Expression levels of a subset of these were lowered after TDP-43 or FUS/TLS depletion in stem cell-derived human neurons and in TDP-43 aggregate-containing motor neurons in sporadic ALS, supporting a common loss-of-function pathway as one component underlying motor neuron death from misregulation of TDP-43 or FUS/TLS.

/pdf/divergent-roles-of-als-linked-proteins-fus-tls-and-tdp-43-qg1kom8lqk.pdf

Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs

Transactivating response region DNA binding protein (TDP-43) is the major protein component of ubiquitinated inclusions found in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions. Two ALS-causing mutants (TDP-43(Q331K) and TDP-43(M337V)), but not wild-type human TDP-43, are shown here to provoke age-dependent, mutant-dependent, progressive motor axon degeneration and motor neuron death when expressed in mice at levels and in a cell type-selective pattern similar to endogenous TDP-43. Mutant TDP-43-dependent degeneration of lower motor neurons occurs without: (i) loss of TDP-43 from the corresponding nuclei, (ii) accumulation of TDP-43 aggregates, and (iii) accumulation of insoluble TDP-43. Computational analysis using splicing-sensitive microarrays demonstrates alterations of endogenous TDP-43-dependent alternative splicing events conferred by both human wild-type and mutant TDP-43(Q331K), but with high levels of mutant TDP-43 preferentially enhancing exon exclusion of some target pre-mRNAs affecting genes involved in neurological transmission and function. Comparison with splicing alterations following TDP-43 depletion demonstrates that TDP-43(Q331K) enhances normal TDP-43 splicing function for some RNA targets but loss-of-function for others. Thus, adult-onset motor neuron disease does not require aggregation or loss of nuclear TDP-43, with ALS-linked mutants producing loss and gain of splicing function of selected RNA targets at an early disease stage.

/pdf/als-linked-tdp-43-mutations-produce-aberrant-rna-splicing-5cv7kno0ec.pdf

Kevin M. Clutario

Papers

Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs

ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43