Organelle

REEP1 at the crossroads of organelle homeostasis and neurodegeneration

Siyue Qin; Lauren Vicuna; Ju Gao — Wed, 08 Apr 2026 00:00:00 +0000

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.

Association of cytochrome c oxidase dysfunction with amyloidosis in Alzheimer's disease and patient-derived cerebral organoids

Tue, 23 Jun 2026 00:00:00 +0000

Patients with Alzheimer’s disease (AD) demonstrate brain mitochondrial dysfunction and energy deficiency that are closely associated with cognitive impairment. Cytochrome c oxidase (CCO), also known as mitochondrial complex IV, is the terminal enzyme in mitochondrial electron transport chain (ETC). Consistent with the pivotal role of CCO in mitochondrial bioenergetics and high demand for energy to sustain neuronal function, CCO dysfunction has been linked to neurological disorders including AD. However, it remains unclear whether mitochondrial CCO dysfunction represents an adaptive response to AD-associated toxic molecules versus a bona fide pathology to promote AD development. In this study, by meta-analysis of publicly available proteomics analysis of post-mortem frontal lobe tissues from four large cohorts of patients with AD we identified loss of key CCO subunits including mitochondrial DNA (mtDNA)- encoded COX1 and COX3 as well as nuclear DNA (nDNA)-encoded COX5A, COX6B1, COX7C, COX8A, and NDUFA4 in patients with AD. Further biochemical analysis using post-mortem frontal lobe tissues showed lowered CCO activity of neuronal mitochondria from patients with AD, suggesting CCO vulnerability and its potential association with amyloidosis in AD. Lastly, in addition to the inverse relationship between neuronal CCO activity and brain amyloidosis in the tested AD cohort, pharmacological inhibition of CCO promoted amyloid production and elevated beta-secretase 1 (BACE1) activity in cerebral organoids derived from human induced pluripotent stem cells (hiPSCs) from one nonAD and one AD subject. The simplest interpretation of the results is that CCO dysfunction in the frontal lobe is a phenotypic mitochondrial change accompanying AD, which may contribute to the development of brain amyloidosis.

Rescue of miRNA export from amyloid-exposed astroglia by Ras homolog enriched in brain (Rheb) protein

Thu, 30 Apr 2026 00:00:00 +0000

Amyloid protein disrupts miRNA activity in astroglial cells by inducing miRNA sequestration in RNA processing bodies or P-bodies, thereby hindering extracellular vesicle-mediated intercellular communication through miRNAs. The mTOR activator Rheb facilitates miRNA recycling and export, mitigating the negative effects of amyloid on miRNA pathways. Additionally, the miRNA-binding protein Syntaxin 5 or STX5 speeds up the miRNA export process, possibly by relocating miRNPs from P-bodies. However, STX5 cannot support miRNA repressive activity or recycling in astroglia exposed to amyloid. Therefore, relocating miRNA out of P-bodies is necessary for export but not sufficient for miRNA reactivation in amyloid beta (Ab)- affected cells. Interestingly, Rheb enhances both miRNA P-body relocalization, reactivation, and export, thereby counteracting amyloid-related disruptions.