Nature Medicine 10, S2–S9 (2004)

Molecular pathways to neurodegeneration

The molecular bases underlying the pathogenesis of neurodegenerative diseases are gradually being disclosed. One problem that investigators face is distinguishing primary from secondary events. Rare, inherited mutations causing familial forms of these disorders have provided important insights into the molecular networks implicated in disease pathogenesis. Increasing evidence indicates that accumulation of aberrant or misfolded proteins, protofibril formation, ubiquitin-proteasome system dysfunction, excitotoxic insult, oxidative and nitrosative stress, mitochondrial injury, synaptic failure, altered metal homeostasis and failure of axonal and dendritic transport represent unifying events in many slowly progressive neurodegenerative disorders.

Ella Bossy-Wetzel¹, Robert Schwarzenbacher² & Stuart A Lipton<sup>1

1</sup> Center for Neuroscience & Aging, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California 92037.

² Program in Bioinformatics & Systems Biology, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California 92037.

Correspondence should be addressed to Ella Bossy-Wetzel ebossy-wetzel@burnham.org or Stuart A Lipton slipton@burnham.org

Published online: 1 July 2004
doi:10.1038/nm1067

AD is the most common neurodegenerative disorder worldwide. Approximately 4.5 million people suffer from this devastating condition in the United States alone. In AD, neurons of the hippocampus and cerebral cortex are selectively lost. Brains of individuals with AD manifest two characteristic lesions: extracellular amyloid (or senile) plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau protein (Fig. 1a)¹. Amyloid plaques contain small, toxic cleavage products (denoted as A40 and A42) of the amyloid precursor protein (APP). The apoE4 (apolipoprotein E4) genotype is a powerful risk factor for developing AD, and it may possibly affect A deposition and neurofibrillary tangle formation².

Fig. 1
		Figure 1 | Histology and structures related to AD.

Mutations in three genes that are inherited in an autosomal dominant fashion have been linked to rare familial, early-onset forms of AD. These genes include those encoding APP, presenilin 1 (PS1) and presenilin 2 (PS2). Although these familiar forms account for only a few cases of AD, one common event in both familial and sporadic types of AD is the increased production and accumulation of the toxic A. This observation led to the 'amyloid cascade hypothesis' that excessive A production is the primary cause of the disease^{3, 4}.

Do plaques and tangles cause AD, or are they simply the telltale remains of earlier, pivotal events that led to the disease? One problem has been that in people with AD the density of amyloid plaques correlates poorly with the severity of dementia³. Furthermore, although neurofibrillary tangles correlate well with decline in cognitive skills, they seem to be a late event and in some cases possibly downstream of A accumulation⁵. Recent findings, however, indicate that dendritic and synaptic injury occur early and that protofibrils and oligomers of A40 and A42, rather than large plaques, cause neuronal dysfunction.

APP is a type I membrane protein and contains a large extracellular region, a transmembrane helix and a short cytoplasmic tail (Fig. 1b). The N-terminal half of APP contains a heparin-binding domain (N-APP), a copper-binding domain (CuBD) and an APP protease inhibitor domain (APPI) (Fig. 1b). The N-APP structure reveals that APP may belong to a superfamily of cysteine-rich growth factors with a putative heparin-binding site⁶. The CuBD structure is homologous to copper chaperones. This domain may regulate dimerization or proteolytic processing, or it may act as a metallotransporter⁷. There is also structural information on the A peptides that originate by proteolytic processing of APP^{8, 9}. Both A40 and A42 adopt variable and partly helical structures dependent on membrane binding, metal chelation and interaction with other peptides. A binds Cu²⁺, Fe²⁺ and Zn²⁺ coordinated by three histidines (His677, His684, His685) and a tyrosine (Tyr681). Metal binding induces a -sheet-like conformational change in A, resulting in enhanced aggregation.

Toxic A originates from regulated intramembrane proteolysis of APP by a complex of secretases (Fig. 1c). The first cleavage of APP is mediated by - or -secretase, releasing most of the extracellular portion of APP as two fragments, APPs- and APPs-, leaving behind the C-terminal membrane bound fragment (Fig. 1c). This portion of APP is then cleaved by a large protein complex, -secretase, at several sites including amino acid (aa) 711 (A40) and at least three additional subsites at aa713 (A42), aa714 (A43) and aa720 (A49) (Fig. 1b). Several mutations in APP, such as the Swedish mutation, cluster at the -secretase cleavage sites; these mutations result in increased amounts of A peptide and protofibril formation¹⁰.

The precise composition of the -secretase complex is still under debate, but PS1, nicastrin, Aph-1 and Pen-2 seem to be required^{11, 12, 13}. PS1 is a transmembrane domain aspartyl protease that cleaves its substrates in the membrane-spanning region. PS1 is probably responsible for the generation of A fragments.

More than 100 missense mutations in PS1 and PS2 have been identified in rare familial, early-onset AD¹⁴. Experiments in culture and transgenic mice reveal that these mutations result in increased A production^{15, 16}. Conversely, mice lacking PS1 have decreased A40 and A42 production^{17, 18}, suggesting that PS1 has a pivotal role in -secretase activity. C-terminal cleavage of APP by caspase enzymes may also be required for toxicity¹⁹.

It is still unclear how A does its damage, but several mechanisms have been proposed. One view suggests that A protofibrils activate microglia, inciting an inflammatory response and release of neurotoxic cytokines. Nonsteroidal anti-inflammatory drugs (NSAIDs) including ibuprofen seem to delay the onset of AD²⁰. Additionally, NSAIDs reduce the production of A42 (ref. 21). In a second view, A protofibrils trigger excessive release of excitatory amino acids like glutamate from glial cells that may injure nearby neurons by excitotoxicity. Overactivation of glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype results in increased intracellular Ca²⁺, which activates neuronal nitric oxide synthase and consequently generates nitric oxide (NO). When generated in excess, NO combines with superoxide anion (O₂^-), forming the highly reactive and neurotoxic product peroxynitrite (ONOO^-), which leads to further oxidative and nitrosative stress in part via mitochondrial injury. In fact, positive phase III human trials of the uncompetitive NMDA receptor channel blocker, memantine, led to its recent approval for the treatment of AD²². A third view suggests that protofibrils and aggregates convey harmful effects to neurons by paralyzing axonal and dendritic transport. Both APP and PS may bind kinesin I and regulate vesicular traffic^{23, 24, 25}. PS mutants increase glycogen synthase kinase-3 activity, which hampers kinesin-mediated, anterograde axonal transport²⁵. Also, A deposits may act as nonspecific 'roadblocks', representing a physical transport barrier.

An additional mechanism of A injury is synaptic dysfunction and loss, which are early events in AD and occur before amyloid plaque formation²⁶. Cholinergic transmission and synaptic density are considerably decreased in AD patients. The mechanism for synaptic damage is unknown, but diffusible oligomeric forms of A may be important. Synaptic dysfunction probably contributes to memory loss and cognitive deficits in AD. In fact, APP transgenic mice manifest cellular, biochemical and electrophysiological evidence of synaptic deficits before A deposition, including reduced excitatory postsynaptic potentials and LONG-TERM POTENTIATION (LTP), regarded as a correlate of learning and memory²⁷. Inhibition of -secretase decreases oligomeric A and LTP deficits²⁸. Microinjection of A43 and A40 peptides into the rat hippocampus disrupts synaptic transmission and short-term memory²⁹.

A may also mediate harmful effects by binding redox-reactive metals, which in turn release free radicals^{30, 31, 32, 33, 34, 35, 36}. We found that nitrosative stress mobilizes zinc from intracellular stores, resulting in mitochondrial dysfunction³⁷. Chelation of zinc and copper provides neuroprotective effects³⁸. For example, clioquinol (CQ), an antibiotic that also chelates zinc and copper and crosses the blood-brain barrier, decreases brain A deposition and improves learning in mutant APP transgenic mice³⁹. A recent human phase II clinical trial of CQ for AD seems promising⁴⁰.

Oxidative stress from mitochondrial dysfunction occurs early in AD, and A may directly or indirectly injure mitochondria^{41, 42}. A blocks respiratory complex I, thus producing a decline in ATP⁴³. In isolated mitochondria, A inhibits respiration and enzyme activity (-ketoglutarate dehydrogenase and pyruvate dehydrogenase)⁴⁴. The mechanism of A translocation to mitochondria remains unknown. New data describe an interaction partner of A in mitochondria, termed A-binding alcohol dehydrogenase (ABAD)⁴⁵. ABAD is upregulated in neurons of AD patients. Expression of ABAD in concert with mutant APP enhances free-radical production and toxicity. Conversely, a peptide that blocks A-ABAD interaction prevents free-radical formation and cell death. A interacts with the LD loop of ABAD, close to its nicotinamide adenine dinucleotide (NAD) binding site, and may therefore induce a conformational change that prevents NAD binding. To date, however, details of the interaction are not apparent in the crystal structure⁴⁵.

One important feature of PD is the presence of eosinophilic, cytoplasmic inclusions of fibrillar, misfolded proteins, termed Lewy bodies, in affected brain areas (Fig. 2a). The exact composition of Lewy bodies is unknown, but they contain ubiquinated -synuclein, parkin, synphilin, neurofilaments and synaptic vesicle proteins (Fig. 2a).

Fig. 2
		Figure 2 | Histology and structures related to PD.

Rare hereditary forms of PD have provided insight into the molecular pathways of this disorder⁴⁷. Mutations in at least four genes have been linked to PD, including -synuclein (PARK1), parkin (PARK2), DJ-1 (PARK7), and PTEN (phosphatase and tensin homolog deleted on chromosome 10)-induced kinase 1 (PINK1, also known as PARK6)^{55, 56, 57, 58}.

-Synuclein mutations are autosomal dominant and represent toxic gain-of-function mutations, resulting in abnormal protein accumulations^{59, 60}. The normal function of -synuclein is unknown. The protein is normally unfolded, revealing little three-dimensional structure. -synuclein can polymerize into filaments and is found in Lewy bodies and neurites (Fig. 2a). The molecular pathways of -synuclein-mediated toxicity are unknown; however, increased oxidative stress, mitochondrial injury and altered cellular transport have been proposed.

Parkin substrates include glycosylated -synuclein, synphilin, CDCrel-1 and the Pael-R receptor. These substrates may accumulate when parkin E3 ligase function is lost by mutation or other mechanism, contributing to neurotoxicity. Overexpression of wild-type parkin improves cell survival after various insults in a number of systems^{64, 65, 66, 67}. Parkin blocks -synuclein- and Pael-R-mediated toxicity, probably by promoting their degradation^{64, 65, 68}. Parkin also mediates the clearance of some polyglutamine repeat proteins⁶⁹. In Drosophila, parkin protects cells from mitochondrial death pathways⁷⁰. Hence, enhancing parkin activity may be therapeutic.

Fig. 3
		Figure 3 | DJ-1 and PINK1 proteins in PD.

HD is an autosomal dominant inherited neurodegenerative disorder affecting 1 in 10,000 individuals. It is caused by an insertion of multiple CAG repeats in the huntingtin gene. This results in an N-terminal polyglutamine (polyQ) expansion of the large protein huntingtin (Htt), similar to other polyQ-related neurodegenerative disorders. Disease severity depends on the length of the polyQ stretch, with repeats 40 clearly linked to HD. The polyQ expansion is thought to confer a toxic gain of function with selective loss of neurons in the striatum and cerebral cortex.

Fig. 4
		Figure 4 | Aggregation and domain structure of Htt in HD.

ALS (or Lou Gehrig's disease) involves degeneration of motor neurons, resulting in progressive muscle wasting and weakness, culminating in paralysis, respiratory failure and death. Perhaps 10% of cases are familial, and of those, 2–3% are caused by mutations in the gene encoding Cu/Zn superoxide dismutase-1 (SOD1), producing a toxic gain of function rather than loss of (catalytic) function¹⁰⁰. The precise pathogenic mechanism is not clear, but implicated in motor neuron dysfunction and death are protein misfolding and aggregation, defective axonal transport, mitochondrial dysfunction and excitotoxicity via faulty glutamate reuptake into glial cells. Recent structural evidence suggests that some Cu/Zn SOD1 mutations result in destabilization of normal dimers of the enzyme and foster aggregation, forming amyloid or pores depending on the conditions, not unlike familial amyloid polyneuropathy^{101, 102}. Stabilization of dimers has therefore been proposed as a therapeutic intervention¹⁰³.

Acknowledgements

We thank Eliezer Masliah and Mark Barsoum for providing histological images, Huaxi Xu for reading the manuscript and our colleagues for helpful discussions. This work was supported by NIH grants R01 NS44314 and R01 NS047456 (to E.B-W.) and P01 HD29587, R01 EY05477, R01 EY09024, R01 NS43242, R01 NS44326 and R01 NS41207 (to S.A.L.).

Competing interests statement:

The authors declare competing financial interests.

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