Genetics of Amyotrophic Lateral Sclerosis

Ghasemi, Mehdi; Brown, Robert H.

doi:10.1101/cshperspect.a024125

Cited by 189 publications

(147 citation statements)

References 206 publications

(141 reference statements)

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“…Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative diseases with shared genetic susceptibilities (Ghasemi and Brown, 2017). ALS primarily leads to the progressive degeneration of motor neurons, while FTD, the second most common cause of early onset dementia after Alzheimer’s disease (AD), is characterized clinically by behavioral abnormalities or language dysfunction with progressive degeneration of the frontal and temporal lobes in the brain (Onyike and Diehl-Schmid, 2013).…”

Section: Introductionmentioning

confidence: 99%

TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging

Jin

Zhu

et al. 2018

Cell

342

301

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Aging is a major risk factor for both genetic and sporadic neurodegenerative disorders. However, it is unclear how aging interacts with genetic predispositions to promote neurodegeneration. Here, we investigate how partial loss of function of TBK1, a major genetic cause for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comorbidity, leads to age-dependent neurodegeneration. We show that TBK1 is an endogenous inhibitor of RIPK1 and the embryonic lethality of Tbk1 mice is dependent on RIPK1 kinase activity. In aging human brains, another endogenous RIPK1 inhibitor, TAK1, exhibits a marked decrease in expression. We show that in Tbk1 mice, the reduced myeloid TAK1 expression promotes all the key hallmarks of ALS/FTD, including neuroinflammation, TDP-43 aggregation, axonal degeneration, neuronal loss, and behavior deficits, which are blocked upon inhibition of RIPK1. Thus, aging facilitates RIPK1 activation by reducing TAK1 expression, which cooperates with genetic risk factors to promote the onset of ALS/FTD.

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Section: Introductionmentioning

confidence: 99%

TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging

Jin

Zhu

et al. 2018

Cell

342

301

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“…Over 180 different mutations in SOD1 have been identified and associated with the disease (Wroe et al, 2008). After the discovery of SOD1, many other genes have been associated with ALS (Ghasemi & Brown, 2017). These genes encode for proteins involved in different cellular pathways, from RNA metabolism, to nuclear transport, to protein and organellar quality control, highlighting the complexity of ALS pathogenesis (Peters et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Parkin is a disease modifier in the mutant SOD 1 mouse model of ALS

et al. 2018

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Mutant Cu/Zn superoxide dismutase (SOD1) causes mitochondrial alterations that contribute to motor neuron demise in amyotrophic lateral sclerosis (ALS). When mitochondria are damaged, cells activate mitochondria quality control (MQC) mechanisms leading to mitophagy. Here, we show that in the spinal cord of G93A mutant SOD1 transgenic mice (SOD1‐G93A mice), the autophagy receptor p62 is recruited to mitochondria and mitophagy is activated. Furthermore, the mitochondrial ubiquitin ligase Parkin and mitochondrial dynamics proteins, such as Miro1, and Mfn2, which are ubiquitinated by Parkin, and the mitochondrial biogenesis regulator PGC1α are depleted. Unexpectedly, Parkin genetic ablation delays disease progression and prolongs survival in SOD1‐G93A mice, as it slows down motor neuron loss and muscle denervation and attenuates the depletion of mitochondrial dynamics proteins and PGC1α. Our results indicate that Parkin is a disease modifier in ALS, because chronic Parkin‐mediated MQC activation depletes mitochondrial dynamics‐related proteins, inhibits mitochondrial biogenesis, and worsens mitochondrial dysfunction.

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“…Moreover, mutations in genes encoding important components of these degradation pathways can cause ALS (Taylor et al, 2016, Ghasemi andBrown, 2018), including UBQLN2 , p62/SQSTM1 , Rubino et al, 2012, Hirano et al, 2013, OPTN (Maruyama et al, 2010), VCP (Johnson et al, 2010), VAPB (Nishimura et al, 2004) and TBK1 (Freischmidt et al, 2015). Taken together, this evidence suggests that ALS-sensitive SpMNs are under proteostatic stress during ALS progression (Atkin et al, 2008, Hetz and Mollereau, 2014.…”

Section: Introductionmentioning

confidence: 94%

Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons

Fujiki

Iannitelli

et al. 2019

Preprint

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In amyotrophic lateral sclerosis (ALS) spinal motor neurons (SpMN) progressively degenerate while a subset of cranial motor neurons (CrMN) are spared until late stages of the disease. Using a rapid and efficient protocol to differentiate mouse embryonic stem cells (ESC) to SpMNs and CrMNs, we now report that ESC-derived CrMNs accumulate less human (h)SOD1 and insoluble p62 than SpMNs over time. ESCderived CrMNs have higher proteasome activity to degrade misfolded proteins and are intrinsically more resistant to chemically-induced proteostatic stress than SpMNs.Chemical and genetic activation of the proteasome rescues SpMN sensitivity to proteostatic stress. In agreement, the hSOD1 G93A mouse model reveals that ALSresistant CrMNs accumulate less insoluble hSOD1 and p62-containing inclusions than SpMNs. Primary-derived ALS-resistant CrMNs are also more resistant than SpMNs to proteostatic stress. Thus, an ESC-based platform has identified a superior capacity to maintain a healthy proteome as a possible mechanism to resist ALS-induced neurodegeneration.

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Genetics of Amyotrophic Lateral Sclerosis

Cited by 189 publications

References 206 publications

TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging

TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging

Parkin is a disease modifier in the mutant SOD 1 mouse model of ALS

Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons

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