Basic mechanisms of neurodegeneration: a critical update

Abstract

Neurodegenerative diseases are characterized by progressive dysfunction of specific populations of neurons, determining clinical presentation. Neuronal loss is associated with extra and intracellular accumulation of misfolded proteins, the hallmarks of many neurodegenerative proteinopathies. Major basic processes include abnormal protein dynamics due to deficiency of the ubiquitin-proteosome-autophagy system, oxidative stress and free radical formation, mitochondrial dysfunction, impaired bioenergetics, dysfunction of neurotrophins, 'neuroinflammatory' processes and (secondary) disruptions of neuronal Golgi apparatus and axonal transport. These interrelated mechanisms lead to programmed cell death is a long run over many years. Neurodegenerative disorders are classified according to known genetic mechanisms or to major components of protein deposits, but recent studies showed both overlap and intraindividual diversities between different phenotypes. Synergistic mechanisms between pathological proteins suggest common pathogenic mechanisms. Animal models and other studies have provided insight into the basic neurodegeneration and cell death programs, offering new ways for future prevention/treatment strategies.

Figures

Fig 1

Algorithm for classification of neurodegenerative diseases with protein deposits (proteinopathies) (from [1]).

Fig 2

Cascade of neurotoxic effects of protein oligomeres leading to neuronal dysfunction/ND; illustrated by the suggested relationship between Aβ and αSyn oligomers.

Fig 3

Model of protein misfolding and fibrillation leading to deposition of aggregated proteins in cells and extracellular spaces via actions of the UPS, phagosomes and aggresomes, either causing cell death or cytoprotection.

Fig 4

Schematic interaction of proteins in neurodegenerative diseases and mitochondria. Accumulation of mitochondrial DNA mutations may induce ROS production and cause oxidative damage in aging. In AD, ROS production and decreased ATP may contribute to production of Aβ peptides that may enter mitochondria, induce free radicals, decrease cytochrome oxidase activity and inhibit ATP generation. APP is transported to outer mitochondrial membranes, blocks import of nuclear cytchrome oxidase proteins to mitchondria, and may decrease cytochrome oxidase activity. In AD and models, Aβ is found in mitochondrial matrix, produces free radicals and causes mitochondrial dysfunction. N-terminal portion of ApoE4, γ-secretase complex proteins, e.g. presenilins and nicastrin, associated with mitochondria, may contribute to Aβ production and cause oxidative damage. In HD neurons, Htt binds to outer mitochondrial membrane und induces free radical production; H2O2 may also interrupt calcium uptake. In PD neurons, mutant proteins of αSyn, Parkin, PINK1 and DJ1 are associated with mitochondria and cause their dysfunction. In ALS, mutant SOD1, localized in inner and outer mitochondrial membranes and matrix, induces oxidative damage; associated with impairment of complexes II and IV. Frataxin, a gene product in FRA, is a mitochondrial protein responsible for heme biosynthesis and formation of iron-sulfur clusters, facilitating the accumulation of iron and inducing free radicals (modified from [257])

Fig 5

Overview of apoptotic signalling through the receptor-mediated (‘extrinsic’) and mitochondria bases (‘intrinsic’) pathways, showing all key molecular players of apoptosis, the importance of the caspase cascade via interaction with different death domaines, and the role of effective caspase driving the execution of the cell death program.

Fig 6

Diverse pathways leading to cell death, illustrated by the concept of the apoptosis-necrosis continuum that integrates the various death pathways and subsequent intracellular signalling pathways (ER stress, UPS, ATP loss, etc.) to help explain the complex patterns of neuronal death (mix of PCD-types I, II and/or III) (modified from [245]).