REEP1 at the crossroads of organelle homeostasis and neurodegeneration

Abstract

Hereditary spastic paraplegia (HSP) is a group of inherited neurodegenerative disorders characterized by progressive spasticity and weakness of the lower limbs, primarily due to degeneration of corticospinal motor neurons. Among the genetic causes of HSP, mutations in Receptor Expression Enhancing Protein 1 (REEP1) are well established, highlighting its critical role in motor system maintenance. Beyond HSP, REEP1 mutations have also been implicated in other motor neuron and neuromuscular diseases, including distal hereditary motor neuropathies (dHMNs), Charcot–Marie–Tooth disease (CMT), and spinal muscular atrophy (SMA). REEP1 is a transmembrane protein with hydrophobic domains and a cytosolic microtubule-binding region that plays a central role in shaping and maintaining intracellular organelles, particularly the endoplasmic reticulum (ER) and mitochondria. In addition, REEP1 contributes to the homeostasis of other organelles and membrane contact sites, including mitochondrial-associated membranes (MAMs), lipid droplets, and endo-lysosomal system. Loss-of-function mutations disrupt organelle morphology and dynamics, resulting in impaired axonal transport, increased cellular stress, and selective vulnerability of motor neurons. By linking fundamental defects in organelle biology to neuromuscular phenotypes, REEP1 provides critical insight into mechanisms of motor system degeneration. This review integrates current knowledge of REEP1 protein structure and functions, emphasizing its role in maintaining organelle homeostasis, and explores how disruption of these mechanisms contributes to neuromuscular and motor neuron disease pathogenesis.