Corrected by having less of key protein DRP1
The structure and function of vital energy producing cell organelles, mitochondria, is commonly significantly impaired in the HSPs. This review describes the regulation of mitochondrial fission and fusion in the link between mitochondrial dynamics and axonal defects in HSP neurons.
Causing there to be less (downregulation) dynamin-related protein 1 (DRP1) either by genetic manipulation or pharmacological means corrected axonal outgrowth defects in the HSP neurons, thus providing a potential therapeutic target for treatment.
Impaired axonal development and degeneration underlie debilitating neurodegenerative diseases including hereditary spastic paraplegia, a large group of inherited diseases. Hereditary spastic paraplegia is caused by retrograde degeneration of the long corticospinal tract axons, leading to progressive spasticity and weakness of leg and hip muscles. There are over 70 subtypes with various underlying pathophysiological processes, such as defective vesicular trafficking, lipid metabolism, organelle shaping, axonal transport, and mitochondrial dysfunction.
Although hereditary spastic paraplegia consists of various subtypes with different pathological characteristics, defects in mitochondrial morphology and function emerge as one of the common cellular themes in hereditary spastic paraplegia. Mitochondrial morphology and function are remodeled by mitochondrial dynamics regulated by several key fission and fusion mediators. However, the role of mitochondrial dynamics in axonal defects of hereditary spastic paraplegia remains largely unknown.
Recently, studies reported perturbed mitochondrial morphology in hereditary spastic paraplegia neurons. Moreover, downregulation of mitochondrial fission regulator dynamin-related protein 1, both pharmacologically and genetically, could rescue axonal outgrowth defects in hereditary spastic paraplegia neurons, providing a potential therapeutic target for treating these hereditary spastic paraplegias.
This mini-review will describe the regulation of mitochondrial fission/fusion, the link between mitochondrial dynamics and axonal defects, and the recent progress on the role of mitochondrial dynamics in axonal defects of hereditary spastic paraplegia.
SOURCE: Neural Regen Res. 2019 Apr;14(4):574-577. doi: 10.4103/1673-5374.248108. PMID: 30632492
Rescue axonal defects by targeting mitochondrial dynamics in hereditary spastic paraplegias.
1 Department of Biomedical Sciences, University of Illinois College of Medicine Rockford, Rockford; Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA.