Intrafamilial Variable Phenotype of Complicated Hereditary Spastic Paraplegia, Ataxia and Motor Neuron Disease Linked to a Novel KIF5A C-Terminal Domain Mutation

2019 ◽  
Author(s):  
Mohammed Faruq ◽  
Deepak Kumar ◽  
Saruchi Wadhwa ◽  
Uzma Shamim ◽  
Aradhana Mathur ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Hereditary Spastic Paraplegia ◽  
Spastic Paraplegia ◽  
Terminal Domain ◽  
Variable Phenotype

Hereditary spastic paraplegia: More than an upper motor neuron disease

2017 ◽  
Vol 173 (5) ◽  
pp. 352-360 ◽  
Author(s):  
L. Parodi ◽  
S. Fenu ◽  
G. Stevanin ◽  
A. Durr
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Hereditary Spastic Paraplegia ◽  
Spastic Paraplegia

Upper Motor Neuron Disorders Hereditary Spastic Paraplegia and Primary Lateral Sclerosis

2017 ◽  
Author(s):  
Sabrina Paganoni ◽  
Nazem Atassi
Keyword(s):  
Motor Neuron ◽  
Hereditary Spastic Paraplegia ◽  
Disease Modeling ◽  
Primary Lateral Sclerosis ◽  
Spastic Paraplegia ◽  
Underlying Pathophysiology ◽  
Primary Lateral ◽  
Lateral Sclerosis

Upper motor neuron (UMN) syndromes are a group of rare, degenerative neurological disorders that are classified as either hereditary spastic paraplegia (HSP) or primary lateral sclerosis (PLS). Our understanding of their underlying pathophysiology is unfortunately very limited and has been a significant barrier to the development of disease-modifying treatments. Recent advances in genetics and in vitro and in vivo disease modeling have provided new insights into disease mechanisms and hold the promise to lead to the future development of mechanism-based therapies.

scholarly journals Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors

2019 ◽  
Author(s):  
Kyoko Chiba ◽  
Chen Min ◽  
Shogo Arai ◽  
Koichi Hashimoto ◽  
Richard J. McKenney ◽  
...  
Keyword(s):  
Motor Activity ◽  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Synaptic Vesicle ◽  
Axonal Transport ◽  
Cell Biology ◽  
Neuronal Morphology ◽  
Loss Of Function ◽  
Spastic Paraplegia ◽  
Anterograde Axonal Transport

AbstractKIF1A is a kinesin-family motor involved in the axonal transport of synaptic vesicle precursors (SVPs) along microtubules. In humans, more than ten point mutations in KIF1A are associated with the motor neuron disease, hereditary spastic paraplegia (SPG). However, not all of these mutations appear to inhibit the motility of the KIF1A motor, and thus, a clear molecular explanation for how KIF1A mutations lead to neuropathy is not available. In this study, we established in vitro motility assays with purified full-length human KIF1A and found that KIF1A mutations associated with the pure form of spastic paraplegia hyperactivate motility of the KIF1A motor. Introduction of the corresponding mutations into Caenorhabditis elegans KIF1A homologue unc-104 revealed abnormal accumulation of SVPs at the tips of axons and increased anterograde axonal transport of SVPs. Our data reveal that hyper-activation of kinesin motor activity, rather than its loss-of-function, is a novel cause of motor neuron disease in humans.Significance StatementAnterograde axonal transport supplies organelles and protein complexes throughout axonal processes to support neuronal morphology and function. It has been observed that reduced anterograde axonal transport is associated with neuronal diseases. In contrast, here we show that particular disease-associated mutations in KIF1A, an anterograde axonal motor for synaptic vesicle precursors, induce hyperactivation of KIF1A motor activity and increased axonal transport of synaptic vesicle precursors. Our results advance the knowledge of the regulation of motor proteins and axonal transport and cell biology of motor neuron diseases.

scholarly journals Upper Motor Neuron Disorders: Primary Lateral Sclerosis, Upper Motor Neuron Dominant Amyotrophic Lateral Sclerosis, and Hereditary Spastic Paraplegia

2021 ◽  
Vol 11 (5) ◽  
pp. 611
Author(s):  
Timothy Fullam ◽  
Jeffrey Statland
Keyword(s):  
Motor Neuron ◽  
Hereditary Spastic Paraplegia ◽  
Diagnostic Tests ◽  
Primary Lateral Sclerosis ◽  
Spastic Paraplegia ◽  
Disease Modifying ◽  
Primary Lateral ◽  
Early Phases ◽  
Lateral Sclerosis ◽  
Motor Neuron Syndrome

Following the exclusion of potentially reversible causes, the differential for those patients presenting with a predominant upper motor neuron syndrome includes primary lateral sclerosis (PLS), hereditary spastic paraplegia (HSP), or upper motor neuron dominant ALS (UMNdALS). Differentiation of these disorders in the early phases of disease remains challenging. While no single clinical or diagnostic tests is specific, there are several developing biomarkers and neuroimaging technologies which may help distinguish PLS from HSP and UMNdALS. Recent consensus diagnostic criteria and use of evolving technologies will allow more precise delineation of PLS from other upper motor neuron disorders and aid in the targeting of potentially disease-modifying therapeutics.

scholarly journals Loss of Function of Glucocerebrosidase GBA2 Is Responsible for Motor Neuron Defects in Hereditary Spastic Paraplegia

2013 ◽  
Vol 92 (2) ◽  
pp. 238-244 ◽  
Author(s):  
Elodie Martin ◽  
Rebecca Schüle ◽  
Katrien Smets ◽  
Agnès Rastetter ◽  
Amir Boukhris ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Hereditary Spastic Paraplegia ◽  
Loss Of Function ◽  
Spastic Paraplegia
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