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<p>Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss in the substantia nigra and α-synuclein (αSyn) accumulation in Lewy bodies. Genetic mutations in upstream regulators of cellular pathways, such as <i>LRRK2</i>, <i>VPS35</i>,<i> TMEM230</i>, and <i>PINK1</i>, are increasingly implicated in dysregulating Rab8a GTPase function, potentially disrupting its roles in αSyn homeostasis, lysosomal clearance, autophagy, membrane trafficking, lipid metabolism, and ciliogenesis. Rab8a protectively interacts with S129-phosphorylated αSyn to promote the formation of less toxic aggregates, whereas its depletion impairs lysosomal function and αSyn degradation. Gain-of-function <i>LRRK2</i> and <i>VPS35</i> mutations phosphorylate Rab8a at threonine 72 (Thr72), exacerbating PD pathology. In contrast, loss-of-function <i>TMEM230</i> mutations have been linked to reduced Rab8a levels in some models, impairing vesicular trafficking and autophagy, whereas loss-of-function <i>PINK1</i> mutations abolish serine 111 (Ser111) phosphorylation in a PINK1-dependent manner. This loss of phosphorylation impairs Rab8a activation (via reduced Rabin8 GEF binding) and removes a regulatory constraint on pathogenic LRRK2-mediated Thr72 phosphorylation. <i>In vivo</i>, <i>LRRK2</i> and <i>PINK1</i> mutations mechanistically converge on striatal ciliogenesis defects, reducing glial-derived neurotrophic factor (GDNF) signaling and neuroprotection. Although preclinical data strongly implicate Rab8a dysregulation as a downstream effector of multiple PD-associated genetic pathways, direct evidence of altered Rab8a expression or phosphorylation in human PD brain tissue is currently lacking. This review emphasizes the emerging role of Rab8a in PD pathogenesis and highlights its therapeutic potential.</p>

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Rab8a dysregulation in Parkinson’s disease: A convergence of genetic and molecular pathologies

  • 期刊论文

  • 发表日期：

    2026年2月27日

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  • Sophie Schuelke,
  • Sana Haseeb,
  • Mayur S. Parmar

摘要

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss in the substantia nigra and α-synuclein (αSyn) accumulation in Lewy bodies. Genetic mutations in upstream regulators of cellular pathways, such as LRRK2, VPS35, TMEM230, and PINK1, are increasingly implicated in dysregulating Rab8a GTPase function, potentially disrupting its roles in αSyn homeostasis, lysosomal clearance, autophagy, membrane trafficking, lipid metabolism, and ciliogenesis. Rab8a protectively interacts with S129-phosphorylated αSyn to promote the formation of less toxic aggregates, whereas its depletion impairs lysosomal function and αSyn degradation. Gain-of-function LRRK2 and VPS35 mutations phosphorylate Rab8a at threonine 72 (Thr72), exacerbating PD pathology. In contrast, loss-of-function TMEM230 mutations have been linked to reduced Rab8a levels in some models, impairing vesicular trafficking and autophagy, whereas loss-of-function PINK1 mutations abolish serine 111 (Ser111) phosphorylation in a PINK1-dependent manner. This loss of phosphorylation impairs Rab8a activation (via reduced Rabin8 GEF binding) and removes a regulatory constraint on pathogenic LRRK2-mediated Thr72 phosphorylation. In vivo, LRRK2 and PINK1 mutations mechanistically converge on striatal ciliogenesis defects, reducing glial-derived neurotrophic factor (GDNF) signaling and neuroprotection. Although preclinical data strongly implicate Rab8a dysregulation as a downstream effector of multiple PD-associated genetic pathways, direct evidence of altered Rab8a expression or phosphorylation in human PD brain tissue is currently lacking. This review emphasizes the emerging role of Rab8a in PD pathogenesis and highlights its therapeutic potential.