Pharmacological activation of the E3 ligase Parkin represents a rational therapeutic intervention for the treatment of Parkinson's disease. We demonstrate how a high-throughput screen with in vitro purified components enabled us to identify small molecule positive allosteric modulators that speed up poly-autoUbiquitination of Parkin. Yet they fail to enhance mitophagy in a cellular milieu. We propose the MOA of activators that work primarily on Parkin and not phospho-Parkin.

Mutations in PINK1, a central regulator of mitochondrial quality control, result in Parkinson’s disease (PD). We screened for PINK1-activating molecules and identified MTK458, which selectively binds PINK1 and promotes mitophagy. Published data show that alpha-synuclein aggregation induces mitochondrial dysfunction; MTK458 treatment drives clearance of pathologic alpha-synuclein both in vitro and in vivo models. Lastly, we identified that PINK1-pathway marker pS65 ubiquitin is significantly increased in PD patient plasma and lowered by MTK458 treatment in mice and rats.

Ophthalmic neuroprotection and axonal regeneration related to the retina and optic nerve are important components of the neurological diseases and their mitigation. It is important to highlight and cross-educate researchers that the eyes are indeed windows to the brain, and in fact the retina and optic nerve serve very useful surrogate models for the greater CNS pathologies.

I will describe our HTT-lowering program that leverages our knowledge of splicing regulation to discover and develop oral systemically distributed small-molecule splicing modifiers.  Utilizing this cutting-edge technology, we identified splicing modifiers that cross the blood-brain-barrier upon oral delivery, and uniformly lower HTT levels in the key affected areas of an HD mouse brain.  The presentation will describe how these molecules were identified and optimized for improved oral bioavailability, penetration of the blood-brain-barrier and potency.

SARM1 (sterile alpha and TIR motif containing 1) is a key executioner of axon degeneration and a therapeutic target for multiple neurodegenerative conditions. We have solved its oligomeric structures, characterised its enzymatic function of NAD+ cleavage and allosteric activation, and uncovered the molecular mechanism of an orthosteric small-molecule inhibitor that was shown to assist recovery of injured axons.

Neurodegeneration disease pathologies include inflammatory reactions, functional loss of neurons in the central nervous system, regional patterns of brain shrinkage and abnormal accumulation of proteinaceous material in and around neurons. The speakers of this session will address the interplay of targeted strategies to prevent these neurodegeneration pathologies in Parkinson's disease and amyotrophic lateral sclerosis (ALS).

Chaperone-mediated autophagy (CMA) contributes to cellular quality control and the cellular response to stress through the selective degradation of cytosolic proteins in lysosomes. Proteins of common neurodegenerative disorders have been shown to undergo degradation via CMA. Here, we identified a unique mechanism for selective activation of CMA and a tractable target for developing CMA activators. Our lead CMA activators demonstrated protection against pathologic stress in various neurodegeneration models.

The LRRK2 gene, encoding leucine-rich repeat kinase 2 (LRRK2), is a common genetic cause of Parkinson’s disease (PD). Genetic variation in LRRK2 also modifies the risk of inflammatory bowel disorders (IBD) and infectious diseases. In this work we aim to better understand the roles of LRRK2 in immune cell signaling pathways and their potential contribution to inflammatory and infectious disorders.

Exportin-1 (XPO1) is a therapeutic target in both amyotrophic lateral sclerosis (ALS) and oncology. I will discuss the development and use ofchemical biology tools to measure XPO1 target occupancy and their application to in vivo models.

Modeling Parkinson’s disease in mice suggests c-Abl activation is required for PD initiation and progression, and therefore inhibition of c-Abl could be a strategy for disease-modification of Parkinson’s. IkT-148009 once daily protected neurons, restored function, reduced pathological alpha-synuclein, and suppressed neuroinflammation in models. 12.5 mg to 325 mg for up to seven days was well-tolerated and exhibited linear dose proportionality, high systemic exposure, and no clinically significant adverse events.

Increasing evidence suggests that the protein aggregates that accumulate in ALS and Alzheimer’s disease proceed via stress granule intermediates.  Approaches developed by Aquinnah Pharmaceuticals has generated pipelines of compounds that target these protein aggregates from an unbiased perspective, with the goal of generating disease modifying therapies. In addition, emerging science around the role of RNA metabolism in stress granule biology identifies additional therapeutic targets for modifying stress granule biology and therefore disease progression.

The NLRP3 inflammasome has recently emerged as a promising therapeutic target for inflammatory diseases. After activation NLRP3 forms a complex with ASC followed by formation of the inflammasome. We optimized a NLRP3-dependent ASC speck formation assay in a murine macrophage line and utilized it to screen a small molecule library. Additional assays to investigate NLRP3 form the basis of a project to identify inhibitors for the treatment of neurodegeneration.

Itanapraced is a brain-penetrant inhibitor of AICD with excellent pharmacokinetics. In clinical studies in MCI patients, itanapraced reduced the concentration of TNF alpha and sCD40 ligand in CSF whilst showing an excellent safety profile over 90 weeks of daily dosing. In vitro and in vivo studies have demonstrated that itanapraced prevents AICD from relocating to the nucleus and acting as a transcriptional regulator. Amongst the genes regulated are Bim, Pink1, and LRRK2. In a LRRK2 mouse model of Parkinson’s disease, itanapraced was able to reduce Parkinson like symptoms.

BioAge is analyzing proprietary human -omics and longitudinal health outcome data to identify novel neurodegeneration drug targets. Our analyses showed that NLRP3 levels rise with age and correlate positively with mortality and cognitive decline. We have synthesized new compounds that inhibit NLRP3 inflammasome in vitro and in vivo, are as or more potent than known NLRP3 inhibitors, have novel structures and chemical properties, and penetrate the blood-brain barrier.