3 years ago

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

Age-Dependent Dopaminergic Neurodegeneration and Impairment of the Autophagy-Lysosomal Pathway in LRRK-Deficient Mice
Youren Tong, Emilie Giaime, Guodong Huang, Jie Shen, Yang Yuan, Lisa K. Wagner

Summary

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.

Publisher URL: http://www.cell.com/neuron/fulltext/S0896-6273(17)30905-4

DOI: 10.1016/j.neuron.2017.09.036

You might also like
Never Miss Important Research

Researcher is an app designed by academics, for academics. Create a personalised feed in two minutes.
Choose from over 15,000 academics journals covering ten research areas then let Researcher deliver you papers tailored to your interests each day.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.