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Northwestern University Feinberg School of Medicine
Krainc Laboratory

Krainc Lab Research

Dopaminergic neurons differentiated from Parkinson’s disease patient-derived induced pluripotent stem cells (iPSCs)
Dopaminergic neurons differentiated from Parkinson’s disease patient-derived induced pluripotent stem cells (iPSCs)

Parkinson’s disease: Examination of converging pathogenic pathways to identify key targets for therapeutic development

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, characterized by progressive degeneration of SNc dopaminergic neurons leading to clinical parkinsonian symptoms (bradykinesia, resting tremors, muscular rigidity, and postural instability). Although the majority of patients do not have a family history of PD (sporadic PD patients), genetic studies have identified several genes which cause familial forms of PD including α-synuclein, LRRK2, VPS35, ATP13A2, PINK1, parkin, DJ-1 and GBA1. Furthermore, brains of sporadic and familial PD patients also show formation of Lewy bodies consisting of α-synuclein deposits, suggesting that α-synuclein accumulation and toxicity is a key player in PD pathogenesis. Our lab studies the function of multiple PD genes and converging cellular mechanisms both upstream and downstream of α-synuclein toxicity in order to ultimately identify new therapeutic targets for PD.

Using patient-derived induced pluripotent stem cells (iPSCs) differentiated into dopaminergic neurons, we have found that:

  1. Upstream dysfunction in multiple PD genes including ATP13A2, parkin, DJ-1 and GBA1 leads to α-synuclein accumulation and defects in both endolysosomal and mitochondrial pathways
  2. Downstream α-synuclein accumulation additionally results in lysosomal dysfunction by disrupting trafficking of multiple lysosomal enzymes including GBA1.

Key Papers

Personalized medicine: Targeting GBA1 in Parkinson’s disease

Our lab is ultimately interested in using patient-specific approaches to target neurodegenerative diseases including Parkinson’s, Huntington’s and Frontotemporal dementia (FTD). To accomplish this, we:

  1. Obtain patient-derived induced pluripotent stem cells (iPSCs) and differentiate them into neurons which we can grow and analyze in long-term cultures. We additionally use genetic sequencing and CRISPR-CAS gene editing technologies to help identify cellular pathways that are disrupted in these neurons.
  2. Use medicinal chemistry to identify small molecule drugs/compounds which can ameliorate these defects and test their efficacy in both cell and animal models.
  3. Bring these compounds we have identified back into the clinic to treat patients with these diseases.

Using patient samples, we have identified an important bidirectional loop between loss of GBA1 function (which causes Gaucher’s disease) and α-synuclein toxicity in Parkinson’s disease. Importantly, we have found that increasing enzymatic activity of the GBA1 protein (β-glucocerebrosidase) reduces α-synuclein accumulation and associated downstream toxicity in human neurons, and are now identifying novel compounds which efficiently target and activate GBA1 in order to reduce α-synuclein toxicity in Parkinson’s disease and other synucleinopathies.

Key Papers

Huntington’s disease: Gene transcription and degradation pathways

Huntington’s disease (HD) is a devastating genetic neurodegenerative disorder caused by polyglutamine (polyQ) expansions in the huntingtin protein, leading to striatal loss and clinical symptoms including chorea. However, the mechanisms through which mutant huntingtin leads to HD are still not completely understood.

We have found that

  1. Mutant huntingtin disrupts cellular transcription pathways which may contribute to neuronal death. Both soluble and non-aggregated mutant huntingtin interfere with transcriptional machinery to repress expression of target genes such as PGC-1α, a master regulator of mitochondrial function. In addition, the NAD-dependent deacetylase Sirt1 plays a neuroprotective role in HD models via its effects on TORC1, a brain-specific modulator of CREB transcriptional activity
  2. Modification of mutant huntingtin by acetylation leads to more efficient degradation of the mutant protein by autophagic/lysosomal degradation pathways. Based on these findings, we are currently identifying novel therapeutic agents which promote acetylation and degradation of mutant huntingtin to potentially prevent cellular death in HD neurons.

Key Papers