Abstract
Neurodegenerative diseases (NDDs) are characterized by selective dysfunction and loss of neurons associated with pathologically altered proteins that deposit in the human brain but also in peripheral organs. These proteins and their biochemical modifications can be potentially targeted for therapy or used as biomarkers. Despite a plethora of modifications demonstrated for different neurodegeneration-related proteins, such as amyloid-β, prion protein, tau, α-synuclein, TAR DNA-binding protein 43 (TDP-43), or fused in sarcoma protein (FUS), molecular classification of NDDs relies on detailed morphological evaluation of protein deposits, their distribution in the brain, and their correlation to clinical symptoms together with specific genetic alterations. A further facet of the neuropathology-based classification is the fact that many protein deposits show a hierarchical involvement of brain regions. This has been shown for Alzheimer and Parkinson disease and some forms of tauopathies and TDP-43 proteinopathies. The present paper aims to summarize current molecular classification of NDDs, focusing on the most relevant biochemical and morphological aspects. Since the combination of proteinopathies is frequent, definition of novel clusters of patients with NDDs needs to be considered in the era of precision medicine. Optimally, neuropathological categorizing of NDDs should be translated into in vivo detectable biomarkers to support better prediction of prognosis and stratification of patients for therapy trials.
Highlights
Neurodegenerative diseases (NDDs) are characterized by progressive dysfunction and loss of neurons leading to distinct involvement of functional systems defining clinical presentations
Neurons are exhausted by converging pathways of altered mitochondria and energy metabolism, voltage-dependent anion channel, and lipid rafts as exemplified in Alzheimer disease (AD) [6]; mitochondrial dysfunction is central in the pathogenesis of Parkinson disease (PD) [7]
Our study using double immunolabelling and immunogold electron microscopy excluded colocalization of phosphorylated (p)Transactive response (TAR) DNA-binding protein 43 (TDP-43) with the endosomal-lysosomal system (ELS) [201], later supported by findings of others using an oligomer TDP-43 antibody [202]. These data somehow contrast the observations on neuronal cytopathology in AD, prion diseases or PD, where the disease-specific proteins are processed within endosomes, and a distinct role of the ELS in motor neuron diseases has been suggested [93,94,136,201,202]
Summary
Neurodegenerative diseases (NDDs) are characterized by progressive dysfunction and loss of neurons leading to distinct involvement of functional systems defining clinical presentations. Oxidative stress and formation of free radicals/reactive oxygen species, mitochondrial dysfunctions, impaired bioenergetics and DNA damage, neuroinflammatory processes and disruption of cellular/axonal transport are linked to the formation of toxic forms of NDD-related proteins [9] These pathways most likely do not represent the “only pathways” leading to neurodegeneration; they are interrelated in a complex way leading to neuronal dysfunction and death. Disease-modifying therapeutic strategies may require reducing the synthesis, preventing the aggregation and/or enhancing the clearance of the pathological forms of proteins [10] These aspects emphasize the importance of protein-based classification of NDDs and its translation into in vivo biomarkers capable of detecting diseases as early as possible. There are a considerable number of possible combinations of proteinopathies, referred to in the frame of mixed pathologies [15]; detailed discussion of these is out of the scope of the present paper
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