An in-depth review article from a consortium of researchers presented evidence for the eight hallmarks of neurodegenerative diseases (NDDs): pathological protein aggregation, synaptic and neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA and RNA defects, inflammation, and neuronal cell death.
Scientists have defined the NDD hallmark as a cellular or molecular process that fulfills the following criteria: (1) Links to (rare) genetic forms of NDDs, (2) Contributes to sporadic forms of NDDs, (3) Contributes to neurodegeneration and neuronal loss in preclinical models and NDD patients, and (4) Molecular markers that are reflective of the hallmark are altered.
The authors described the genetic and biological evidence of these features, and highlighted the inter-relationships between the underlying cellular and molecular processes. They also reported on how hallmarks can be detected and monitored using in vivo biomarkers.
The authors then analyzed these characteristics and their evidence in the context of prevalent NDDs, including Alzheimer’s disease, Parkinson’s disease, primary tauopathies, frontotemporal dementia, amyotrophic lateral sclerosis, synucleinopathies (i.e., Lewy body dementia and multisystem atrophy), Huntington’s disease and related polyglutamine diseases (including spinocerebellar ataxias), prion disease, traumatic brain injury, chronic traumatic encephalopathy, stroke, spinal cord injury and multiple sclerosis.
The authors proposed that the neurodegenerative process in NDDs is caused by combining defects in multiple NDD hallmarks, indicating the need for multi-targeted therapies. They recommended that this framework could be used to understand the molecular mechanisms of neurodegeneration, to categorize various NDDs according to their primary hallmarks, to stratify subtypes and patients within specific NDDs based on the primary hallmarks, and to design combinatorial or personalized therapeutic strategies to effectively stop NDDs.
This article was published in the scientific journal Cell. Wilson DM et al. Hallmarks of neurodegenerative diseases. Cell 186, February 16, 2023 (Open Access) https://doi.org/10.1016/j.cell.2022.12.032