Converging pathways in neurodegeneration, from genetics to mechanisms

Abstract

Neurodegenerative diseases cause progressive loss of cognitive and/or motor function and pose major challenges for societies with rapidly aging populations. Human genetics studies have shown that disease-causing rare mutations and risk-associated common alleles overlap in different neurodegenerative disorders. Here we review the intricate genotype-phenotype relationships and common cellular pathways emerging from recent genetic and mechanistic studies. Shared pathological mechanisms include defective protein quality-control and degradation pathways, dysfunctional mitochondrial homeostasis, stress granules, and maladaptive innate immune responses. Research efforts have started to bear fruit, as shown by recent treatment successes and an encouraging therapeutic outlook.

Fig. 1|. Primary brain regions affected in major neurodegenerative diseases.

Clinical manifestations reflect distinct and overlapping neuronal circuits that progressively degenerate in various neurodegenerative diseases.

Fig. 2|. Common neuronal pathways altered in multiple neurodegenerative diseases, including protein quality control, the autophagy-lysosome pathway, mitochondria homeostasis, protein seeding and propagation of stress granules, and synaptic toxicity and network dysfunction.

Inset I: molecular chaperones, including HSP, regulate protein folding and ubiquitin-proteasome system (UPS)-mediated degradation, while disaggregase could return misfolded proteins to their natively folded and functional state. Inset II: dysfunction in the autophagy-lysosomal pathway could underlie accumulation of pathogenic protein aggregates and damaged mitochondria. Inset III: impairment of mitochondrial quality control through mitophagy and mitochondrial dynamics results in reduced energy production and dysfunctional proteostasis network. Inset IV: transcellular propagation and seeding of protein aggregates could underlie the disease progression. Inset V: abnormal stress granule dynamics that favor aggregation and aberrant incorporation of misfolded proteins contributes to toxicity. Inset VI: soluble forms of protein assemblies induce both pre- and postsynaptic impairments, leading to network dysfunction. HSP; heat shock protein.

Fig. 3|. Innate immune pathways in neurodegenerative diseases.

A maladaptive innate immune response has emerged as a critical driving force in the pathogenesis of many neurodegenerative diseases. SNPs on many disease-associate genes induce maladaptive innate immune responses that are also associated with aging and epigenetic changes. Microglia, the resident immune cells in the brain, engage in crosstalk with astroglia and are modulated by peripheral immune system. Maladaptive microglia could damage neuronal circuits due to dysfunction in their detection or response to homeostasis imbalance, resulting in accumulation of protein aggregates, in concert with astroglia and possibly the peripheral immune system. Microglia could also cause neuronal and network dysfunction by altering cytokine signaling and synaptic pruning, independently of their effects on protein aggregates.