Abstract
Cellular control of vesicle biology and trafficking is critical for cell viability, with disruption of these pathways within the cells of the central nervous system resulting in neurodegeneration and disease. The past two decades have provided important insights into both the genetic and biological links between vesicle trafficking and neurodegeneration. In this essay, the pathways that have emerged as being critical for neuronal survival in the human brain will be discussed – illustrating the diversity of proteins and cellular events with three molecular case studies drawn from different neurological diseases.
Highlights
Neurodegenerative diseases, characterised by the progressive loss of neurons in the central nervous system, impact on the lives of millions of people around the world [1]
• Genes identified in Mendelian forms of neurodegeneration
• The biological basis for these deficits are an area of particular interest with regard
Summary
Neurodegenerative diseases, characterised by the progressive loss of neurons in the central nervous system, impact on the lives of millions of people around the world [1]. The progressive loss of motor neurons is a defining pathological characteristic for a heterogeneous group of neurological disorders including, amongst others, amyotrophic lateral sclerosis, spinal muscular atrophy and the hereditary spastic paraplegias [26–28] Across this spectrum of disease, mutations in a large number of genes have been identified with one of the many areas highlighted being proteins with specific functions in vesicular trafficking – prominent examples being the SPAST gene involved in the regulation of microtubule dynamics and the ATL1 gene, both of which have been heavily implicated in vesicle trafficking centred around the endoplasmic reticulum [29]. Autosomal dominant mutations in the DNAJC5 gene, encoding cysteine string protein α, cause a hereditary form of neuronal ceroid lipofuscinosis – a form of lysosomal storage disorder characterised by the accumulation of lipofuscin within the cells of the central nervous system [49] This results in neurodegeneration and a complex clinical phenotype, including parkinsonism in some patients. Achieving specificity in the central nervous system, and avoiding potentially deleterious on target impacts outside of the brain, remains a major challenge
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