ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function

Baron, Desiree M.; Fenton, Adam R.; Sáez-Atiénzar, Sara; Giampetruzzi, Anthony; Sreeram, Aparna; Shankaracharya, _; Keagle, Pamela; Doocy, Victoria R; Smith, Nathan J.; Danielson, Eric; Andresano, Megan; McCormack, Mary C; Garcia, Jaqueline; Bercier, Valérie; Bosch, Ludo Van Den; Brent, Jonathan Robert; Fallini, Claudia; Traynor, Bryan J.; Holzbaur, Erika L.F.; Landers, John E.

doi:10.1016/j.celrep.2022.110598

Cited by 66 publications

(62 citation statements)

References 117 publications

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“…NOVA1 and NOVA2 were ~1.5 fold enriched in SPG11-HSP. However, the degree of significance of enrichment was at least ~10 5 fold lower in SPG11-HSP compared to the ALS datasets (Fig. 2l).…”

Section: Nova1 Nova2 and Rbfox2 Are Associated With Alternative Splic...mentioning

confidence: 92%

Aberrant NOVA1 function disrupts alternative splicing in early stages of amyotrophic lateral sclerosis

et al. 2022

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Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by aberrant alternative splicing (AS). Nuclear loss and cytoplasmic accumulation of the splicing factor TDP-43 in motor neurons (MN) are hallmarks of ALS at late stages of the disease. However, it is unknown if altered AS is present before TDP-43 pathology occurs. Here, we investigate altered AS and its origins in early stages of ALS using human induced pluripotent stem cell-derived motor neurons (MNs) from sporadic and familial ALS patients. We find high levels of the RNA-binding proteins NOVA1, NOVA2, and RBFOX2 in the insoluble protein fractions and observe that AS events in ALS-associated MNs are enriched for binding sites of these proteins. Our study points to an early disrupted function of NOVA1 that drives AS changes in a complex fashion, including events caused by a consistent loss of NOVA1 function. NOVA1 exhibits increased cytoplasmic protein levels in early stage MNs without TDP-43 pathology in ALS postmortem tissue. As nuclear TDP-43 protein level depletes, NOVA1 is reduced. Potential indications for a reduction of NOVA1 also came from mice over-expressing TDP-43 lacking its nuclear localization signal and iPSC-MN stressed with puromycin. This study highlights that additional RBP-RNA perturbations in ALS occur in parallel to TDP-43.

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“…NOVA1 and NOVA2 were ~1.5 fold enriched in SPG11-HSP. However, the degree of significance of enrichment was at least ~10 5 fold lower in SPG11-HSP compared to the ALS datasets (Fig. 2l).…”

Section: Nova1 Nova2 and Rbfox2 Are Associated With Alternative Splic...mentioning

confidence: 92%

Aberrant NOVA1 function disrupts alternative splicing in early stages of amyotrophic lateral sclerosis

et al. 2022

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“…Recently, multiple studies indicate that an ALS-causing mutation (Δexon27) that changes the C-terminus of KIF5A is a gain-of-function mutation that leads to a loss of autoinhibition (Baron et al, 2022; Nakano et al, 2022) (Pant et al, 2022 bioRxiv). Since the mutation creates a new C-terminus, it needs to be further addressed whether it is the loss of autoinhibition per se or the creation of a new C-terminus that leads to ALS.…”

Section: Resultsmentioning

confidence: 99%

“…Cytoplasmic dynein is the minus-end-directed microtubule motor, and defects in dynein and/or its regulator dynactin have been implicated in ALS (Chevalier-Larsen and Holzbaur, 2006; LaMonte et al, 2002; Maimon et al, 2021; Münch et al, 2004). Some vesicular cargos bind both dynein and kinesin-1 via the same cargo adapter (Cox and Spradling, 2006; Fenton et al, 2021; Fu and Holzbaur, 2014)(Canty et al, 2021, bioRxiv; Celestino et al, 2021, bioRxiv), and in this case, loss of kinesin-1 autoinhibition may help overcome the force of dynein to change cargo distribution (Baron et al, 2022; Kelliher et al, 2018). Interestingly, in many cell types including filamentous fungi, mammalian neurons, C. elegans neurons, and Drosophila oocytes, dynein itself is a cargo of kinesin-1 (Arimoto et al, 2011; Brendza et al, 2002; Duncan and Warrior, 2002; Egan et al, 2012; Hirokawa et al, 1990; Januschke et al, 2002; Lenz et al, 2006; Twelvetrees et al, 2016; Yamada et al, 2010; Zhang et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…An important aspect of kinesin-1 regulation is its autoinhibition that involves the interaction between the C-terminal tail and the motor domains (Cai et al, 2007; Chiba et al, 2022; Coy et al, 1999; Dietrich et al, 2008; Friedman and Vale, 1999; Kaan et al, 2011; Seiler et al, 2000; Stock et al, 1999; Verhey and Hammond, 2009; Wong et al, 2009). Recently, an exon27-skipping mutation (Δexon27) in the KIF5A kinesin-1 that causes the devastating neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS) has been linked to a loss of autoinhibition (Baron et al, 2022; Nakano et al, 2022; Pant et al, 2022). However, the functional significance of kinesin-1 autoinhibition in normal cells would need to be further dissected.…”

Section: Introductionmentioning

confidence: 99%

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Kinesin-1 autoinhibition facilitates the initiation of dynein cargo transport

Qiu

Zhang

Xiang

2022

Preprint

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Kinesin-1 undergoes autoinhibition but its functional significance has been unclear. Kinesin-1 transports multiple cargoes including cytoplasmic dynein to the microtubule plus ends. From a genetic screen for Aspergills mutants defective in dynein-mediated early endosome transport, we identified a kinesin-1 mutation kinAK895* that disrupts kinesin-1 autoinhibition. Consistent with kinAK895* making kinesin-1 constitutively active, the mutant proteins accumulate abnormally near the microtubule plus ends. Unexpectedly, our genetic data show that kinesin-1 autoinhibition is unnecessary for transporting its cargoes such as secretory vesicles. Dynein accumulates normally at the microtubule plus ends in the kinAK895* mutant. However, the frequency but not the speed of dynein-mediated early endosome transport is significantly decreased, indicating that kinesin-1 autoinhibition facilitates dynein to initiate its cargo transport. Furthermore, kinesin-1 autoinhibition promotes dynein cargo initiation in a way mechanistically distinct from LIS1-promoted dynein switching from its autoinhibited form. Thus, while dynein activation involves dynactin, cargo adapter and LIS1, this study adds kinesin-1 autoinhibition as a new regulatory factor in vivo.

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“…Recently, de novo frameshift mutations causing exon 27 skipping (ΔExon27) and downstream elongation of the KIF5A tail have been reported to abolish KIF5A ability to perform autoinhibition, leading to aberrant mitochondrial transport along axons, and to enhance mutant KIF5A interaction with SQSTM1/p62 (Baron et al 2022 ). Therefore, neurodegeneration caused by ΔExon27 KIF5A mutations seems to be linked to a toxic GOF disrupting neuronal trafficking and homeostasis.…”

Section: Autophagic Genes Involved In Alsmentioning

confidence: 99%

Autophagy Dysfunction in ALS: from Transport to Protein Degradation

Cozzi

Ferrari

2022

J Mol Neurosci

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons (MNs). Since the identification of the first ALS mutation in 1993, more than 40 genes have been associated with the disorder. The most frequent genetic causes of ALS are represented by mutated genes whose products challenge proteostasis, becoming unable to properly fold and consequently aggregating into inclusions that impose proteotoxic stress on affected cells. In this context, increasing evidence supports the central role played by autophagy dysfunctions in the pathogenesis of ALS. Indeed, in early stages of disease, high levels of proteins involved in autophagy are present in ALS MNs; but at the same time, with neurodegeneration progression, autophagy-mediated degradation decreases, often as a result of the accumulation of toxic protein aggregates in affected cells. Autophagy is a complex multistep pathway that has a central role in maintaining cellular homeostasis. Several proteins are involved in its tight regulation, and importantly a relevant fraction of ALS-related genes encodes products that directly take part in autophagy, further underlining the relevance of this key protein degradation system in disease onset and progression. In this review, we report the most relevant findings concerning ALS genes whose products are involved in the several steps of the autophagic pathway, from phagophore formation to autophagosome maturation and transport and finally to substrate degradation.

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ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function

Cited by 66 publications

References 117 publications

Aberrant NOVA1 function disrupts alternative splicing in early stages of amyotrophic lateral sclerosis

Aberrant NOVA1 function disrupts alternative splicing in early stages of amyotrophic lateral sclerosis

Kinesin-1 autoinhibition facilitates the initiation of dynein cargo transport

Autophagy Dysfunction in ALS: from Transport to Protein Degradation

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