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Age-Dependent Dopaminergic Neurodegeneration and Impairment of the Autophagy-Lysosomal Pathway in LRRK-Deficient Mice.

Neuron | Nov 15, 2017

LRRK2 mutations are the most common genetic cause of Parkinson's disease, but LRRK2's normal physiological role in the brain is unclear. Here, we show that inactivation of LRRK2 and its functional homolog LRRK1 results in earlier mortality and age-dependent, selective neurodegeneration. Loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and of noradrenergic neurons in the locus coeruleus is accompanied with increases in apoptosis, whereas the cerebral cortex and cerebellum are unaffected. Furthermore, selective age-dependent neurodegeneration is only present in LRRK-/-, not LRRK1-/- or LRRK2-/- brains, and it is accompanied by increases in α-synuclein and impairment of the autophagy-lysosomal pathway. Quantitative electron microscopy (EM) analysis revealed age-dependent increases of autophagic vacuoles in the SNpc of LRRK-/- mice before the onset of DA neuron loss. These findings revealed an essential role of LRRK in the survival of DA neurons and in the regulation of the autophagy-lysosomal pathway in the aging brain.

Pubmed ID: 29056298 RIS Download

Mesh terms: Adrenergic Neurons | Aging | Animals | Autophagy | Cerebellum | Cerebral Cortex | Dopaminergic Neurons | Female | Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 | Locus Coeruleus | Male | Mice | Mice, Knockout | Mutation | Nerve Degeneration | Protein-Serine-Threonine Kinases | Signal Transduction | Substantia Nigra | Vacuoles | alpha-Synuclein

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Associated grants

  • Agency: NINDS NIH HHS, Id: P50 NS094733
  • Agency: NINDS NIH HHS, Id: R01 NS071251
  • Agency: NINDS NIH HHS, Id: R37 NS071251

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