Northwestern University Feinberg School of Medicine

Simpson Querrey Center for Neurogenetics

Accumulation of Aggregates in Lysosomal Storage Disease

Current Observations

The recurrent observation of accumulation and aggregation of mutant proteins such as α-synuclein, Tau, Aβ in different neurodegenerative disorders indicates the possibility of a shared mechanism. Recent data suggest that elimination of mutant protein accumulation can halt the symptomatic progression and also lead to regression of the disease. (1-4)

The number of inherited adult-onset neurodegenerative diseases caused by proteins that regulate protein sorting and degradation within the endocytic and lysosomal pathways has recently grown considerably. These diseases are classified across the lifespan as disorders of lysosomal function, which feature extensive accumulations of misfolded proteins in the central nervous system and share the same traits of neurodegeneration observed in PD, AD and related disorders.

Center for Neurogenetics' Approach

These findings indicate that if proteins such as α-synuclein can somehow be cleared, the disease can be prevented or even reversed. The clearance of aggregation-prone proteins is largely achieved through the autophagy-lysosomal system. The main challenge is to identify key mechanisms and targets involved in the clearance of these proteins in order to develop specific therapeutics. To tackle this challenge, we propose to examine rare lysosomal storage disorders that commonly exhibit neurodegeneration and are caused by mutations in genes involved in lysosomal function. These rare diseases offer an exciting opportunity for therapeutic development in the field of neurodegeneration by targeting specific proteins involved in lysosomal function.

Referenced Publications

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

  1. Krainc, D. Clearance of mutant proteins as a therapeutic target in neurodegenerative diseases.  Archives in Neurology. 2010, 67(4):388-92. PMID: 20385902
  2. Yamamoto, A., Lucas, J.J., and Hen, R. (2000). Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell 101, 57-66. PMID: 10778856 
  3. Zu, T., Duvick, L.A., Kaytor, M.D., Berlinger, M.S., Zoghbi, H.Y., Clark, H.B., and Orr, H.T. (2004). Recovery from polyglutamine-induced neurodegeneration in conditional SCA1 transgenic mice. J Neurosci 24, 8853. PMID: 15470152
  4. Lim Y, Kehm VM, Lee EB, Soper JH, Li C, Trojanowski JQ, Lee VM. α-Syn suppression reverses synaptic and memory defects in a mouse model of dementia with Lewy bodies. J Neurosci. 2011 Jul 6;31(27):10076. PMID: 21734300
  5. Devine MJ, Gwinn K, Singleton A, Hardy J. Parkinson's disease and α-synuclein expression. Mov Disord. 2011 Oct;26(12):2160-8. PMID: 21887711
  6. Levine, B., and Kroemer, G. (2008). Autophagy in the Pathogenesis of Disease. Cell 132, 27-42. PMID: 18191218 
  7. Bellettato CM, Scarpa M. Pathophysiology of neuropathic lysosomal storage disorders. J Inherit Metab Dis. 2010 Aug;33(4):347-62. PMID: 20429032
  8. Mazzulli, J.R., Sun, Y., Knight, A.L., McLean, P.J., Caldwell, G, Sidransky, E, Grabowski, G.A. and Krainc, D. Gaucher’s Disease Glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011 Jul 8;146(1):37-52. (Accompanied by the Perspective in Cell, Science Translational Medicine, and Editors’ Choice in Science) PMID: 21700325 
  9. Shachar T, Lo Bianco C, Recchia A, Wiessner C, Raas-Rothschild A, Futerman AH. Lysosomal storage disorders and Parkinson's disease: Gaucher disease and beyond. Mov Disord. 2011 Aug 1;26(9):1593-604. PMID: 21618611