Northwestern University Feinberg School of Medicine

Center for Rare Neurological Diseases

Convergence of Lysosomal and Mitochondrial Pathways in Neurodegeneration

Current Observations

Recent data suggest that lysosomes are required for the clearance and turnover of dysfunctional mitochondria (1-3). Many studies have implicated mitochondrial dysfunction in the pathogenesis of neurodegenerative disorders, most strikingly in PD where a recent emergence of genetic forms (e.g. PINK1, Parkin, DJ-1) clearly suggests that dysfunctional mitochondria play a role in PD. Accumulation of damaged mitochondria generates reactive oxygen species (ROS), and oxidized and nitrated α-synuclein has been well documented in PD brain, and can affect the aggregation of α-synuclein (4).

CRND Approach

We propose that lysosomal dysfunction interferes with the clearance of damaged mitochondria and that the two critical pathways, lysosomal dysfunction and mitochondrial dysfunction converge in the pathogenesis of neurodegeneration. Therefore, we suggest that boosting lysosomal function, either alone or in conjunction with improvements in mitochondrial function will have a neuroprotective effect in PD and related disorders.

Referenced Publications

Following is a list of publications referenced in the development of our position and approach.

  1. Youle, R. J. & Narendra, D. P. Mechanisms of mitophagy. Nat Rev Mol Cell Biol 12, 9-14, (2011).
  2. Soubannier V, McLelland GL, Zunino R, Braschi E, Rippstein P, Fon EA, McBride HM. A vesicular transport pathway shuttles cargo from mitochondria to lysosomes. Curr Biol. 2012 Jan 24;22(2):135-41.
  3. Banerjee, R., Starkov, A. A., Beal, M. F. & Thomas, B. Mitochondrial dysfunction in the limelight of Parkinson's disease  pathogenesis. Biochim Biophys Acta1792, 651-663, (2009).
  4. Giasson, B. I., Duda JE, Murray IV, Chen Q, Souza JM, Hurtig HI, Ischiropoulos H, Trojanowski JQ, LeeVM. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290, 985-989, (2000).
  5. Kriks, S., Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z, Carrillo-Reid L, Auyeung G, Antonacci C, Buch A, Yang L, Beal MF, Surmeier DJ, Kordower JH, Tabar V, Studer L. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature, 480, 547-551, (2011).