Abstract
Hereditary Spastic Paraplegias (HSPs) are a genetically diverse group of inherited neurological diseases with over 80 associated gene loci. Over the last decade, research into mechanisms underlying HSPs has led to an emerging interest in lysosome dysfunction. In this review, we highlight the different classes of HSPs that have been linked to lysosome defects: (1) a subset of complex HSPs where mutations in lysosomal genes are causally linked to the diseases, (2) other complex HSPs where mutation in genes encoding membrane trafficking adaptors lead to lysosomal defects, and (3) a subset of HSPs where mutations affect genes encoding proteins whose function is primarily linked to a different cellular component or organelle such as microtubule severing and Endoplasmic Reticulum-shaping, while also altering to lysosomes. Interestingly, aberrant axonal lysosomes, associated with the latter two subsets of HSPs, are a key feature observed in other neurodegenerative diseases such as Alzheimer’s disease. We discuss how altered lysosome function and trafficking may be a critical contributor to HSP pathology and highlight the need for examining these features in the cortico-spinal motor neurons of HSP mutant models.
Highlights
Hereditary Spastic Paraplegias (HSPs) are among the most genetically diverse inherited neurological diseases, with over 80 disease loci identified to date [1]
Category 2 involves complex HSPs where the associated genes do not directly encode lysosomal proteins, but rather proteins involved in membrane trafficking whose loss of function appears to lead to defects in lysosomes
This includes HSPs associated with mutations in genes encoding the Adaptor protein-4 (AP-4) complex
Summary
Hereditary Spastic Paraplegias (HSPs) are among the most genetically diverse inherited neurological diseases, with over 80 disease loci identified to date [1]. Category 1 is a subset of complex HSPs with autosomal recessive inheritance where the causal mutation is in genes encoding lysosomal proteins. These are characterized by progressive spastic paraplegia along with thinning of the corpus callosum, white matter abnormalities, and cognitive impairment. Category 2 involves complex HSPs where the associated genes do not directly encode lysosomal proteins, but rather proteins involved in membrane trafficking whose loss of function appears to lead to defects in lysosomes. The last category (Category 3; Table 1) involves HSPs where the mutant proteins have well-established roles in other pathways and at other organelles This includes mutations in a gene encoding microtubule severing protein, Spastin, whose deregulation is the most common cause of HSP. AD: Autosomal Dominant; AR: Autosomal Recessive; Pure: Spasticity alone; Complex: includes other neurological features in addition to spasticity
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