Journal of Neural Transmission

, Volume 116, Issue 9, pp 1111–1162 | Cite as

Recent advances in our understanding of neurodegeneration

  • Kurt A. JellingerEmail author
Movement Disorders - Review Article


Neurodegenerative diseases are featured by progressive dysfunction and death of cells in selected areas in the nervous system, determining clinical presentation. Neuronal loss is associated with conformational changes in proteins that result in extra- and intra-cellular accumulation of misfolded proteins, representing the hallmarks of many neurodegenerative disorders, summarized as proteinopathies. Intermediate forms such as oligomers and protofibrils are thought to have cytotoxic effects to neurons. Major basic processes, caused by genetic, environmental, and endogenous factors, in addition to abnormal protein dynamics with defective degradation due to deficiency of the ubiquitin–proteosomal–autophagy system, include oxidative stress and free radical formation, impaired bioenergetics and mitochondrial dysfunction, disruption of neuronal Golgi apparatus and transport, molecular chaperones, neurotrophins and “neuroinflammatory” processes. These mechanisms are interrelated in vicious circles finally leading to programmed cell death. A common feature of these conditions is a long run until sufficient protein accumulates, followed by a cascade of symptoms over many years with increasing disability leading to death. This provides a wide therapeutic window, especially in groups at risk identified early and preclinical diagnosis becomes feasible. Neurodegenerative disorders are classified according to known genetic mechanisms or to the major components of protein deposits. Although this has been a productive paradigm for the development of diagnostic consensus criteria, recent molecular biologic and genetic approaches have revealed that there are both overlap and intraindividual diversities between different phenotypes, related to synergistic mechanisms between major pathologic proteins (β-amyloid, tau, α-synuclein, TDP-43), suggesting common pathogenic mechanisms. The nature, time course, and molecular causes of cell degeneration and demise, and the role of various pathogenic factors are a matter of considerable debate, but recent studies have provided insight into the basic processes in neurodegeneration and the roles of cell death programs common to this complex group of disorders, offering new ways for future prevention and treatment strategies.


Neurodegeneration Classification of proteinopathies Pathogenic factors Oxidative stress Bioenergetic deficiency Mitochondrial defects Neuronal dysfunction/death 





Aβ-binding dehydrogenase



Autophagic cell death


Acetylcholine receptor


Alzheimer disease


Advanced glycation endproduct


Apoptosis-inducing factor


Autophagy–lysosome pathway


Amyotrophic lateral sclerosis


Amyloid precursor protein


Apoptosis-related protein




Brain-derived neurotrophic factor


Base excision repairs


Cerebral amyloid angiopathy


Cyclin-dependent kinase 5


Casein kinase 1


Chaperon-mediated autophagy








Deoxyribonucleic acid


Death receptor G


Dynamin-related protein


Endoplasmic reticulum




Fas-associated death domain


Friedreich’s ataxia




Frontotemporal lobe dementia


Golgi apparatus


Trinucleotide repeat




Glutathione peroxide


Reduced glutathione


Huntington disease


Hydroxy-binding protein






Heat shock protein




Lewy body




Leucine-rich repeat kinase 2


Mitogen-activated protein kinase


Mild cognitive impairment


Major histocompatibility complex


Mutant huntingtin


Micro RNA




Mitochondrial permeability transition




Messenger RNA


Multiple system atrophy


Mitochondrial DNA


Mitochondrial RNA




Neurodegenerative disorder/disease


Nuclear DNA




Neurofibrillary tangle


Neuronal growth factor


N-methyl d-aspartate


Nitric oxide


Neurotrophin receptor


Neurotrophic tyrosine kinase


Oxidative stress


Oxidative phosphorylation system


Programmed cell death


Parkinson disease




Peroxisomal proliferation-activated receptor


Protein phosphate 1




(hyper-) Phosphorylated tau


Permeability transition pore


Receptor for AGE


Ribonucleic acid


Reactive nitrogen species


Reactive oxidative species




Serum amyloid component P


Spinocerebellar atrophy


Substantia nigra/compacta


Superoxide dismutase




Tyrosine hydroxylase




Ubiquitin-binding domaine


Unfolded protein reaction


Ubiquitin–proteasome system





The author thanks Mr. E. Mitter-Ferstl, PhD, for secretarial and computer work. The study was supported by the Society for Support of Research in Experimental Neurology, Vienna, Austria.


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© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Institute of Clinical NeurobiologyViennaAustria

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