Lysosomal Dysfunctions in Hereditary Spastic Paraplegias

Abstract

Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of inherited neurodegenerative diseases with the cardinal feature of a length-dependent degeneration of corticospinal motor axons. They are classified by their mapped genetic loci, SPG1-SPG78. Recently, lysosomal dysfunction is one of the pathomechanism for some autosomalrecessive HSPs. SPG11 is caused by loss-of-function mutations in the SPG11 gene. Its gene product is called spatacsin, which is needed for the recycling of lysosomes from autolysosomes. SPG15 is caused by loss-of-function mutation in the ZFYVE26 gene. The ZFYVE26 gene encodes spastizin. Mutations in spastizin impair autophagosome maturation and lead to an accumulation of immature autophagosomes. SPG48/KIAA0415 encodes AP5Z1, known to be a spatacsin and spastizin interactor. Its mutations lead to loss of protein or mutated forms of protein with defective autophagy. The TECPR2 is a human ATG8-binding protein and positive regulator of autophagy, which plays a key role in major adult and pediatric neurodegenerative diseases. Mutations in the lysosomal trafficking regulator (LYST) gene have been reported to cause hereditary spastic paraplegia. The LYST protein is involved in control of the exocytosis of secretory lysosomes. Recently, Drosophila with a gene mutation of an LYST homolog was revealed to exhibit impaired autophagy.

Genetic Investigation of Consanguineous Pakistani Families Segregating Rare Spinocerebellar Disorders

“…ZFYVE26 encodes a zinc-finger protein spastizin that is highly expressed in the brain and is a component of the adaptor-related protein complex 5 (AP5) that plays a crucial role in autophagic lysosomal reformation. Its dysfunctioning can result in the loss of neuronal cells [23,24]. Our study reports the second identified case of ZFYVE26 related spinocerebellar degeneration in the Pakistani population [25].…”