Research Article: Characterization of kinesin switch I mutations that cause hereditary spastic paraplegia

Date Published: July 5, 2017

Publisher: Public Library of Science

Author(s): Scott Jennings, Madeline Chenevert, Liqiong Liu, Madhusoodanan Mottamal, Edward J. Wojcik, Thomas M. Huckaba, Alexander F. Palazzo.

http://doi.org/10.1371/journal.pone.0180353

Abstract

Kif5A is a neuronally-enriched isoform of the Kinesin-1 family of cellular transport motors. 23 separate mutations in the motor domain of Kif5A have been identified in patients with the complicated form of hereditary spastic paraplegia (HSP). We performed in vitro assays on dimeric recombinant Kif5A with HSP-causing mutations in the Switch I domain, which participates in the coordination and hydrolysis of ATP by kinesin. We observed a variety of significantly reduced catalytic and mechanical activities as a result of each mutation, with the shared phenotype from each that motility was significantly reduced. Substitution of Mn2+ for Mg2+ in our reaction buffers provides a dose-dependent rescue in both the catalytic and ensemble mechanical properties of the S203C mutant. This work provides mechanistic insight into the cause of HSP in patients with these mutations and points to future experiments to further dissect the root cause of this disease.

Partial Text

Hereditary Spastic Paraplegia (HSP) is a genetically and clinically heterogeneous disease that involves the progressive degeneration of axons in the corticospinal tract [1–3]. To date, 76 distinct genetic loci and 59 separate human genes have been implicated in the onset of HSP [4]. HSP manifests in either the simple or complicated form of the disease. While progressive lower limb spasticity is common in both forms, patients with the complicated form of HSP may also present with retinopathy, ataxia, peripheral polyneuropathy, and cognitive deficit [5, 6]. Approximately 10% of the known cases of complicated HSP are caused by mutations in the neuronally-enriched, kinesin-1 family member Kif5A [6].

The current therapy to treat patients with HSP is a regimen of muscle relaxants and physical therapy. While this can be effective in helping to alleviate the manifestations of the disease, it addresses neither the mechanistic cause of the disease nor its progressive nature. Targeted therapeutics will require a fundamental understanding of the pathology behind the limb spasticity that all HSP patients share. This project is part of a larger effort to give mechanistic understanding to the disease such that the functional deficit associated with Kif5A mutations can be better understood [40], as well as the cellular loss of function that results [41, 42]. In particular, we have focused on the cluster of mutations in the Switch I motif to generate a mechanistic understanding of the role of this region as it relates to the functional deficit of Kif5A in the presence of HSP-causing mutations. We have shown that each mutation has a significant impact on at least one of the critical aspects of kinesin function, although there is variability in the severity of the decreased activity depending on the individual mutation.

 

Source:

http://doi.org/10.1371/journal.pone.0180353

 

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