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Apoptosis in neurodegenerative disorders

Abstract

Neuronal death underlies the symptoms of many human neurological disorders, including Alzheimer's, Parkinson's and Huntington's diseases, stroke, and amyotrophic lateral sclerosis. The identification of specific genetic and environmental factors responsible for these diseases has bolstered evidence for a shared pathway of neuronal death — apoptosis — involving oxidative stress, perturbed calcium homeostasis, mitochondrial dysfunction and activation of cysteine proteases called caspases. These death cascades are counteracted by survival signals, which suppress oxyradicals and stabilize calcium homeostasis and mitochondrial function. With the identification of mechanisms that either promote or prevent neuronal apoptosis come new approaches for preventing and treating neurodegenerative disorders.

Key Points

  • Neuronal death underlies the symptoms of many human neurological disorders, including Alzheimer's, Parkinson's and Huntington's diseases, stroke, and amyotrophic lateral sclerosis.

  • Many signals can initiate apoptosis in neurons, including lack of neurotrophic factor support, overactivation of glutamate receptors (leading to calcium influx), increased oxidative stress and metabolic stress.

  • Mitochondrial changes are pivotal in the cell death decision in many cases. Mitochondria in cells undergoing apoptosis show increased oxyradical production, opening of pores in their membranes and release of cytochrome c.

  • The Bcl-2 family of proteins includes both anti-apoptotic (for example, Bcl-2) and pro-apoptotic (for example, Bax) members.

  • Overexpression of Bcl-2 in cell cultures and in transgenic mice increases resistance of neurons to death induced by excitotoxic, metabolic and oxidative insults. Conversely, neurons lacking Bax are protected against apoptosis.

  • Further mechanisms that can regulate the early stages of apoptosis in neurons involve caspases (evolutionarily conserved cysteine proteases central to apoptosis of many cell types), Par-4 and telomerase.

  • Neurotrophic factors can protect neurons against apoptosis by activating receptors linked to production of cell survival-promoting proteins (such as antioxidant enzymes, Bcl-2 family members and proteins involved in calcium homeostasis) through kinase cascades.

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Figure 1: Morphological and biochemical features of apoptosis.
Figure 2: Brain regions in which neurodegenerative conditions are typified by selective apoptosis of neurons.
Figure 3: Roles for altered synaptic signalling in neurodegenerative disorders.
Figure 4: Brain tissue section from the hippocampus of a patient who died with Alzheimer's disease.
Figure 5: Mechanisms underlying the pro-apoptotic actions of altered APP processing and presenilin-1 mutations.

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DATABASE LINKS

Bcl-2

Bcl-xL

Bax

Bad

caspase-8

caspase-3

BDNF

NGF

bFGF

TNF-α

CNTF

LIF

CREB

NCKAP1

APP

presenilins 1 and 2

GDNF

IGF-1

ENCYCLOPEDIA OF LIFE SCIENCES

Alzheimer disease

Apoptosis: molecular mechanisms

Glossary

SYNAPTOGENESIS

The process of formation of synapses, the sites where neurons communicate through release of neurotransmitters from the presynaptic terminal and activation of receptors on the postsynaptic neuron.

NEUROTROPHIC FACTORS

Proteins produced by neurons and glial cells that promote neuron survival and growth.

METABOLIC STRESS

Conditions in which levels of glucose, oxygen and other molecules required for ATP (energy) production are decreased.

LEUCINE ZIPPER

A leucine-rich domain within a protein that binds to other proteins with a similar domain.

MICROGLIA

Phagocytic immune cells in the brain that engulf and remove cells that have undergone apoptosis.

EXCITOTOXINS

Compounds such as glutamate, kainic acid and N-methyl-d-aspartate that can kill neurons by activating excitatory amino-acid (glutamate) receptors.

LIMBIC STRUCTURES

Brain structures such as the hippocampus, amygdala and septum that function in learning and memory, and in emotions.

NEURITES

Generic name for processes (axons and dendrites) elaborated from neuronal cell bodies.

SYNAPTOSOME

A structure consisting of pre- and postsynaptic terminals prepared from homogenized brain tissue with cellular fractionation techniques.

SUBSTANTIA NIGRA

A part of the midbrain that contains dopamine-producing neurons whose axons innervate the striatum and thereby control body movements.

MITOCHONDRIAL COMPLEX I

A group of proteins located at the inner mitochondrial membrane that function very early in the electron transport chain.

LEWY BODIES

Eosinophilic, cytoplasmic neuronal inclusions that contain aggregates of the proteins α-synuclein and ubiquitin.

LYMPHOBLASTS

Bone-marrow-derived cells that give rise to lymphocytes.

INTRANEURONAL INCLUSIONS

Aggregates of proteins that accumulate in neurons within the cytoplasm or nucleus.

INFARCT

Brain tissue surrounding the site of a stroke in which cells die.

ISCHAEMIC PENUMBRA

A region of tissue surrounding the necrotic core of an ischaemic infarct in which neurons die primarily by apoptosis.

OLIGODENDROCYTES

A specific type of glial cell, which forms myelin membranes that insulate axons of neurons and thereby increase impulse conduction velocity.

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Mattson, M. Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 1, 120–130 (2000). https://doi.org/10.1038/35040009

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  • DOI: https://doi.org/10.1038/35040009

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