ALS ‐linked KIF5A ΔExon27 mutant causes neuronal toxicity through gain‐of‐function

Abstract

Mutations in the human kinesin family member 5A (KIF5A) gene were recently identified as a genetic cause of amyotrophic lateral sclerosis (ALS). Several KIF5A ALS variants cause exon 27 skipping and are predicted to produce motor proteins with an altered C‐terminal tail (referred to as ΔExon27). However, the underlying pathogenic mechanism is still unknown. Here, we confirm the expression of KIF5A mutant proteins in patient iPSC‐derived motor neurons. We perform a comprehensive analysis of ΔExon27 at the single‐molecule, cellular, and organism levels. Our results show that ΔExon27 is prone to form cytoplasmic aggregates and is neurotoxic. The mutation relieves motor autoinhibition and increases motor self‐association, leading to drastically enhanced processivity on microtubules. Finally, ectopic expression of ΔExon27 in Drosophila melanogaster causes wing defects, motor impairment, paralysis, and premature death. Our results suggest gain‐of‐function as an underlying disease mechanism in KIF5A‐associated ALS.

In Silico Exploration of Metabolically Active Peptides as Potential Therapeutic Agents against Amyotrophic Lateral Sclerosis

“…An in vitro study has found that oligomerization occurs mostly by KIF5A rather than KIF5B and KIF5C [ 44 ]. It has been suggested that some unknown proteins could bind to the abnormal C-terminus of KIF5A (∆exon27) and trigger hyperactivation and aggregation, which changes cellular metabolisms and causes neuronal death [ 45 , 46 ].…”

Condensate functionalization with microtubule motors directs their nucleation in space and allows manipulating RNA localization

“…As a perspective, it would be highly relevant to investigate how the condensation of motor proteins, through multivalent interactions, may contribute to physiological or pathological mechanisms. For instance, a recent study demonstrated that the ALS‐linked KIF5A ΔExon27 mutant, which enhances multimeric self‐interactions of KIF5A proteins, leads to its accumulation in neurotoxic micrometric aggregates localized at the cell periphery (Pant et al , 2022).…”

Kinesin-1 autoinhibition facilitates the initiation of dynein cargo transport

“…Recent studies indicate that an ALS-causing mutation of KIF5A is a gain-of-function mutation disrupting autoinhibition (Baron et al, 2022;Nakano et al, 2022;Pant et al, 2022). In A. nidulans, kinA K895 * or kinA -GFP is also a gain-of-function mutation affecting dynein-mediated early endosome transport in the presence of wild-type kinA (Fig.…”

“…As dynein defects are linked to ALS (Chevalier-Larsen and Holzbaur, 2006; Liu and Henty-Ridilla, 2022), a defect in dynein-mediated transport could possibly contributes to the KIF5A-mutation-caused ALS. It is worthwhile to test this idea and other potential factors including aggregation of uninhibited kinesins or possible changes of microtubules (Baron et al, 2022;Budaitis et al, 2022;Chiba et al, 2022;Kawano et al, 2022;Nakano et al, 2022;Pant et al, 2022).…”

“…An important aspect of kinesin-1 regulation is its autoinhibition that involves an interaction between the C-terminal tails and 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;Weijman et al, 2022;Wong et al, 2009). Recently, a KIF5A (kinesin-1) mutation causing the 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 importance of kinesin-1 autoinhibition in normal cells needs to be dissected.…”