The overarching goal of Krainc group has been to define key molecular pathways in the pathogenesis of neurodegeneration. They have focused on pathogenic mechanisms that are commonly altered in neurodegenerative disorders such as deficient degradation of aggregation-prone proteins and mitochondrial dysfunction. As a general strategy, they study rare genetic diseases with mutations in genes that play a role in these key mechanisms and pathways. Models of Huntington’s, Parkinson’s and Gaucher disease have been utilized to examine if activation of cellular degradation pathways and/or modifications of mutant proteins can lead to protection in these disorders.

Studies of Huntington disease (HD) revealed that mutant huntingtin interferes with specific components of transcriptional machinery to repress expression of target genes such as PGC-1alpha, an important regulator of mitochondrial function (Dunah et al. Science 2002; Zhao et al, Cell, 2004; Cui et al., Cell 2006). Mutant huntingtin also inhibits enzymatic activity of NAD-dependent deacetylase Sirt1 which leads to deregulation of known Sirt1 targets (Jiang et al, Nature Medicine, 2011) and of novel Sirt1 target TORC1, a brain-specific modulator of CREB transcriptional activity (Jeong et al, Nature Medicine, 2011). Since Sirt1 exhibits neuroprotection in several neurodegenerative disorders, it is of interest to examine which Sirt1-mediated pathways play a more general role in neurodegeneration.

While these studies suggested that the soluble mutant protein represents the toxic moiety, aggregation of mutant proteins serves as a marker of inefficient degradation in neurodegenerative disorders and other proteinopathies. Models of HD, Parkinson’s disease, Gaucher disease and Hutchinson-Gilford Progeria have been utilized to examine if activation of cellular degradation pathways and/or modifications of mutant proteins can lead to protection in these disorders. In HD, modification of mutant huntingtin by acetylation resulted in more efficient degradation of the mutant protein by autophagic/lysosomal degradation pathways (Jeong et al, Cell, 2009), suggesting that novel therapeutic agents that promote acetylation and degradation of the mutant protein could provide beneficial in HD. Studies of Hutchinson-Gilford progeria suggested that general upregulation of autophagic/lysosomal pathway dramatically reversed the pathologic phenotype in patient cells (Cao et al, Science Translational Medicine, 2011).

The importance of autophagic/lysosomal pathways in neurodegeneration has been further highlighted by a link between lysosomal storage disorder, Gaucher disease (GD) and PD. GD patients and their relatives have increased risk for PD, and people with PD or idiopathic parkinsonism are more likely to carry glucocerebrosidase gene (GBA) mutations that cause Gaucher’s. The drop in lysosomal GBA causes a buildup of glucosylceramide, which stabilizes toxic alpha-synuclein oligomers. On the other hand, the accumulation of alpha-synuclein further inhibits trafficking of GBA from ER to Golgi, leading to a positive feedback loop between alpha-synuclein and glucocerebrosidase that could lead to a self-propagating disease (Mazzulli et al, Cell, 2011). These data suggested that improved targeting of glucocerebrosidase to lysosomes could represent a specific therapeutic target for PD and other synucleinopathies.

Ongoing projects in the lab are further delineating the connection between lysosomal dysfunction and neurodegeneration, by examining mechanistically how other lysosomal storage disorders lead to neurodegeneration and accumulation of disease-linked proteins.

To validate and study these findings in human neurons, induced pluripotent stem cells (iPS) generated by reprogramming of patient-specific skin fibroblasts have been utilized. These iPS cells are differentiated into specific neuronal subtypes in order to study converging pathways of mitochondrial and lysosomal dysfunction in Parkinson’s disease and related neurodegenerative disorders (Seibler et al, J. Neuroscience, 2011; Mazzulli et al, Cell, 2011). In collaboration with the PD iPS Consortium (http://pdips.org), novel technologies have been developed to further characterize the contribution of genetic, epigenetic and environmental factors to distinct neuronal phenotypes in iPS neurons and their relevance for therapeutic development in Parkinson’s and related disorders.

2007-2011 GENEPARK Consortium (FP6). The main goal of the GENEPARK consortium was employ innovative approaches to determine gene expression profiles specific for genetic and idiopathic Parkinson’s disease (PD) patients. The responsibilities of Krainc group were to perform genome-wide expression profiling of blood samples from PD patients, together with analysis and validation of the subset of newly-identified genes.