Neurodegenerative diseases caused by hereditary or idiosyncratic neuronal
dysfunction share some phenotypic commonalities. Intracellular aggregation of
proteins, metal dyshomeostasis, generic loss of synaptic connectivity all lead to gradual
decline of cognitive or motor neuronal function as patients descend into a clinically
symptomatic state. Though significant progress has been made in our understanding of
neurological disorders in the past decade, it has yet to translate into therapeutic
advancements in disease treatment.
We have chosen to focus this review on Alzheimer’s disease (AD) to highlight the main
disease modifying mechanisms shared in common with the Huntington’s (HD) and
Parkinson’s disease (PD) phenotypes, specifically, the aggregation of amyloid-β (Aβ)
phospho-tau (p-tau), mutant huntingtin (mHtt) and α -synuclein (α-syn) proteins,
respectively. We highlight a number of approaches used in pre-clinical drug discovery
to identify clinical tools. In addition, we describe a number of less explored alternative
hypotheses which have demonstrated good (pre)clinical evidence for a potential
therapeutic intervention.
In particular, for AD, we will review the main concepts which have driven drug
discovery research in the recent past and for each molecular target, we summarize a
rationale and available validation data with commentary on relevant chemical matter
and structural biology, then discuss advanced pre-clinical and clinical compounds.
Keywords: Alzheimer’s disease, amyloid-β, autophagy, Huntington’s disease,
lewy bodies, mutant huntingtin, neurodegeneration, Parkinson’s disease,
physiochemical properties, pre-clinical drug discovery, reactive oxygen species,
α-synuclein, tau.
