1.1. Brief overview of the neurodegenerative diseases
Neurodegenerative diseases are characterized by the progressive loss of neuron populations. These disorders afflict all age groups. There are rare childhood neurodegenerations, neurodegenerations that present in early or mid-adulthood, and others that manifest in late-life. The latter neurodegenerations are particularly common. A case can be made that among the oldest old it is more common to have a neurodegenerative disease than it is to not have one [1
Individual neurodegenerative diseases are defined on both clinical and pathological levels. Diagnoses are most reliable when a specific, recognizable clinical syndrome occurs in conjunction with specific brain histopathology. Diagnostic limitations arise from the fact that substantial clinical overlap exists between some disorders, clinical presentations are occasionally atypical or simply hard to characterize, and various pathologic features may co-exist in the brains of affected patients. The neurodegenerative disorder dementia with Lewy bodies (DLB) is a straightforward example of this. Dementia is a central feature of DLB, and parkinsonism is a frequently cited core feature [2
]. Patients diagnosed with DLB often fulfill clinical criteria for both Alzheimer’s disease (AD) and Parkinson’s disease (PD). Their brains also show neuritic plaques and neurofibrillary tangles, findings typically associated with AD, as well as Lewy bodies, which are typically associated with PD.
In addition to clinical and pathology overlap, molecular overlap also occurs. One recurrent theme is protein aggregation. Protein aggregation can occur extracellularly, in the cytosol, in the nucleus, or in combination. Amyloid plaques are examples of extracellular protein aggregation. In AD, plaques contain the beta amyloid (Aβ) protein, which is itself produced through the enzymatic digestion of the larger amyloid precursor protein (APP). Diseases with amyloid aggregation qualify as “amyloidoses”.
Tau, tar binding protein 43 (TDP43), and synuclein form cytosolic aggregations. Tau comprises the “tangles” seen in multiple neurodegenerative diseases including AD, frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). TDP43 aggregation occurs in FTD and amyotrophic lateral sclerosis (ALS). Synuclein, the primary constituent of Lewy bodies, aggregates in PD, DLB, and muti-system atrophy (MSA). Synuclein is also found extracellularly in AD plaques. These disorders may be variably classified as “tauopathies”, “TDP43-opathies”, and “synucleinopathies”. Nuclear aggregations can occur in neurodegenerative diseases caused by triple repeat expansions. For example, in Hungtington’s disease (HD), huntingtin protein (htt) aggregates in neuron nuclei.
Another recurrent molecular theme in neurodegenerative diseases is mitochondrial perturbation. Observed mitochondrial perturbations are believed to associate with mitochondrial dysfunction. The role mitochondrial perturbation plays in neurodegenerative diseases is sometimes unclear and may differ from disease to disease. In some disorders it appears to initiate neuronal dysfunction and ultimately degeneration. In others it possibly plays an intermediary but unique contributory role. Occasionally, it may represent a generic but still important consequence of more upstream cascades. The term “neurodegenerative mitochondriopathies” was previously proposed to categorize neurodegenerative diseases that feature mitochondrial perturbation [3
]. The following section provides a brief overview of mitochondrial defects seen in various neurodegenerative diseases.
1.2. Mitochondrial perturbation occurs in multiple neurodegenerative diseases
In general, mitochondrial perturbation can arise in several ways. Mutations in mitochondrial DNA (mtDNA) genes, mutations in nuclear genes encoding mitochondrial proteins, and defects in intergenomic signaling can all interfere with mitochondrial function. Gain of function mutations in proteins that normally have no or limited mitochondrial interaction may cause them to directly or indirectly hinder mitochondrial function. Loss of function mutations may deprive mitochondria of necessary support. Changes in the cytosolic milieu may also disrupt mitochondria. Functional defects may involve transport of proteins and substrates into and out of the mitochondria, or else substrate utilization. Mitochondrial perturbations may be fairly non-specific or specific. Examples of non-specific changes include mitochondrial depolarization, enlargement, and ultrastructure changes. Examples of specific defects include diseases in which one but not other respiratory enzymes have altered function.
Both specific and non-specific mitochondrial perturbations are observed in AD [5
]. The most specific defect involves a reduction in the complex IV (cytochrome oxidase) Vmax activity [6
]. This defect is seen in brains and non-degenerating tissues of AD patients. Most studies suggest Vmax activities of other electron transport chain (ETC) enzymes are normal. When mitochondria from AD or control subject platelets are transferred to mtDNA-depleted, respiratory-incompetent cells to form cytoplasmic hybrid (cybrid) cell lines, respiratory function is restored but the cytochrome oxidase Vmax activity in cybrid lines containing AD subject mtDNA is less than it is in cyrid lines containing control subject mtDNA [7
]. This suggests the AD cytochrome oxidase defect arises from mtDNA, although the exact AD mtDNA problem is unclear. Other forms of AD mitochondrial dysfunction are documented, including reductions in the pyruvate dehydrogenase complex Vmax and the ketoglutarate dehydrogenase Vmax [5
]. Oxidative stress is increased in AD subject tissues, and may reflect mitochondrial dysfunction. AD brains also show altered mitochdondrial ultrastructure, increased levels of the 5 KB “common” mtDNA deletion, reduced numbers of intact mitochondria, increased numbers of degrading mitochondria, and altered mitochondrial fission-fusion dynamics [10
From a cause-and-effect perspective AD is particularly perplexing because more than one type of AD may exist [1
]. Rare autosomal dominant cases that arise from APP mutations can be modeled in genetically altered mice via overexpression of a mutated human APP transgene (tg2576 mice). Mitochondrial physiology is altered in these mice. One early change indicates mitochondrial proliferation, which suggests expression of the mutant transgene negatively impacts mitochondrial performance and induces a compensatory response [12
]. Similar results were more recently reported from triple transgenic mice that also express mutant presenilin 1 and tau transgenes [13
]. Other studies indicate in tg2576 mice Aβ interferes with the mitochondrial permeability transition as well as the function of the mitochondrial abeta-binding alcohol dehydrogenase (ABAD) enzyme [14
]. In humans, APP is found in the mitochondrial membrane and Aβ is found inside the mitochondria [16
]. However, it has also been shown that mitochondrial dysfunction can increase Aβ production [19
]. Some propose that in sporadic, late onset AD upstream mitochondrial dysfunction may account for a downstream amyloidosis [21
PD also is characterized by specific and non-specific mitochondrial perturbations. Complex I activity is consistently found to be reduced both in the brains and peripheral tissues of PD patients, while activities of other ETC enzymes are generally not [4
]. The PD complex I defect is believed to be particularly relevant since complex I inhibition produces parkinsonism and dopaminergic neurons appear particularly vulnerable to complex I inhibition [25
]. Similar to what is seen in AD, when mitochondria from PD subject platelets are used to produce cybrid cell lines, respiratory function is restored but the complex I Vmax activity is less than in cybrid lines containing control subject mtDNA [7
]. This suggests the PD complex I defect arises from mtDNA. Although the exact PD mtDNA problem is unclear, PD subject substantia nigra neurons have increased levels of mtDNA deletions and their brains show microheteroplasmic mutations in specific stretches of the mtDNA ND5 gene [30
]. Oxidative stress markers are elevated in PD subject tissues, and cybrid studies further suggest this arises as a consequence of complex I dysfunction [7
PD, like AD, is etiologically heterogeneous with at least one common sporadic form and a number of rare Mendelian forms. Mutations that cause several of the Mendelian forms affect proteins that either localize to mitochondria or otherwise appear to influence mitochondrial function [35
Other sporadic neurodegenerative diseases are associated with specific ETC Vmax reductions. Amyotrophic lateral sclerosis is most generally associated with complex I dysfunction, although reduced cytochrome oxidase Vmax activities are occasionally reported [36
]. PSP cybrids have a complex I Vmax defect, which suggests PSP subjects should themselves have reduced complex I activity [38
]. Oxidative stress is increased in both these diseases. Mitochondrial dysfunction is also implicated in numerous Mendelian neurodegenerations. Multiple ETC Vmax activities are reportedly reduced in HD [40
]. It is unclear whether htt mutation disrupts mitochondrial function by directly interacting with the organelles themselves, or indirectly by affecting other proteins or genes that impact mitochondrial function [41
]. Frataxin, the mutated gene that causes Friedreich’s ataxia (FA), encodes a protein that plays a role in mitochondrial iron homeostasis [43
Neurodegeneration occurs in various mitochondrial encephalomyopathy disorders that are caused by specific mtDNA mutations [4
]. The mitochondrial encephalomyopathies tend to occur in childhood or early adulthood. One of the best characterized mtDNA diseases is Leber’s hereditary optic neuropathy (LHON), a neuroanatomically discrete neurodegenerative disease of the optic nerve.
The list of neurodegenerative mitochondriopathies is long and these disorders are more comprehensively described elsewhere [4
]. Even from this brief overview, though, it is clear that mitochondrial perturbation is a common theme in neurodegenerative diseases. For disorders that qualify as neurodegenerative mitochondriopathies, pursuing treatment development strategies that target mitochondria or processes affected by mitochondria seems reasonable [3