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Journal of Neural Transmission

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

Recent advances in our understanding of neurodegeneration

  • Kurt A. Jellinger
Movement Disorders - Review Article

Abstract

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.

Keywords

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

Abbreviations

8-HOG

8-Hydroxydeoxyguanosine

ABAD

Aβ-binding dehydrogenase

β-Amyloid

ACD

Autophagic cell death

AChR

Acetylcholine receptor

AD

Alzheimer disease

AGE

Advanced glycation endproduct

AIF

Apoptosis-inducing factor

ALP

Autophagy–lysosome pathway

ALS

Amyotrophic lateral sclerosis

APP

Amyloid precursor protein

ARP

Apoptosis-related protein

αSyn

α-Synuclein

BDNF

Brain-derived neurotrophic factor

BER

Base excision repairs

CAA

Cerebral amyloid angiopathy

Cdk5

Cyclin-dependent kinase 5

CK1

Casein kinase 1

CMA

Chaperon-mediated autophagy

Csp

Caspase

Cu

Copper

DA

Dopamine

DNA

Deoxyribonucleic acid

DRG

Death receptor G

DRP

Dynamin-related protein

ER

Endoplasmic reticulum

f

Familial

FADD

Fas-associated death domain

FDRA

Friedreich’s ataxia

Fe

Iron

FTLD

Frontotemporal lobe dementia

GA

Golgi apparatus

GAG

Trinucleotide repeat

GOF

Gain-of-function

GP

Glutathione peroxide

GSH

Reduced glutathione

HD

Huntington disease

HDI

Hydroxy-binding protein

HNE

Hydroxynonenal

htt

Huntingtin

HSP

Heat shock protein

IL

Interleukin

LB

Lewy body

LOF

Loss-of-function

LRRK2

Leucine-rich repeat kinase 2

MAPK

Mitogen-activated protein kinase

MCI

Mild cognitive impairment

MHC

Major histocompatibility complex

mhtt

Mutant huntingtin

miRNA

Micro RNA

MPP+

1-Methyl-4-phenylpyridinium

MPT

Mitochondrial permeability transition

MPTP

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

mRNA

Messenger RNA

MSA

Multiple system atrophy

mtDNA

Mitochondrial DNA

mtRNA

Mitochondrial RNA

ND

Neurodegeneration

NDD

Neurodegenerative disorder/disease

nDNA

Nuclear DNA

NFL

Neurofilament

NFT

Neurofibrillary tangle

NGF

Neuronal growth factor

NMDA

N-methyl d-aspartate

NO

Nitric oxide

NTR

Neurotrophin receptor

NTRK

Neurotrophic tyrosine kinase

OS

Oxidative stress

OxPhoS

Oxidative phosphorylation system

PCD

Programmed cell death

PD

Parkinson disease

polyQ

Polyglutamine

PPAR

Peroxisomal proliferation-activated receptor

PP1

Protein phosphate 1

PSEN

Presenilin

pTau

(hyper-) Phosphorylated tau

PTP

Permeability transition pore

RAGE

Receptor for AGE

RNA

Ribonucleic acid

RNC

Reactive nitrogen species

ROS

Reactive oxidative species

s

Sporadic

SAP

Serum amyloid component P

SCA

Spinocerebellar atrophy

SN/SNc

Substantia nigra/compacta

SOD

Superoxide dismutase

tg

Transgene

TH

Tyrosine hydroxylase

Ub

Ubiquitin

UBD

Ubiquitin-binding domaine

UPR

Unfolded protein reaction

UPS

Ubiquitin–proteasome system

Zn

Zinc

Notes

Acknowledgments

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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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Institute of Clinical NeurobiologyViennaAustria

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