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Pathways to Primary Neurodegenerative Disease

  • John Hardy
    Correspondence
    Individual reprints of this article are not available. Address correspondence to John Hardy, PhD, Department of Research, Mayo Clinic Jacksonville, 4500 San Pablo Rd, Jacksonville, FL 32224
    Affiliations
    Department of Research, Mayo Clinic Jacksonville, Jacksonville, Fla
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      The major neurodegenerative diseases, such as Alzheimer disease, Parkinson disease, the frontal temporal dementias (which overlap with what has historically been called Pick disease), and the prion diseases, are of growing interest, especially in developed societies whose populations have ever-increasing numbers of elderly persons. The causes and pathogeneses of these diseases remain poorly understood. However, during the past few years, the application of molecular genetics and molecular biology has facilitated the beginning of a clearer understanding of the development of these diseases.
      This enhanced understanding has led to the realization that there are unexpected similarities and overlaps among these diseases. These likely reflect overlaps in the pathogenic mechanisms that underlie the neurodegenerative processes in each of these conditions. In this speculative review, I attempt to synthesize our knowledge about these neurodegenerative diseases and to suggest a mechanistic classification that has implications in the understanding and treatment of these conditions.
      In all these diseases, a proportion of the cases have a simple genetic cause, and mutations lead to disease through an autosomal dominant process. I believe that these simple versions of the diseases offer a general insight into the pathogenic mechanisms.
      In Alzheimer disease, mutations in the amyloid precursor protein (APP) gene or the presenilin 1 and presenilin 2 (PS1 and PS2) genes can lead to disease.
      • Goate A
      • Chartler-Harlin MC
      • Mullan M
      • et al.
      Segregation of a missense mutation in the amyloid precursor prolein gene with familial Alzhcimer's disease.
      • Sherringlon R
      • Rogaev IEI
      • Liang Y
      • et al.
      Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.
      • Levy-Lahad E
      • Waseo W
      • Poorkaj P
      • et al.
      Candidate gene for the chromosome I familial Alzheimer's disease locus.
      In Parkinson disease, α-synuclein is 1 of the pathogenic loci.
      • Polymeropoulos MH
      • Lavedan C
      • Leroy E
      • et al.
      Mutation in the alpha-synudcin gene identified in families with Parkinson's disease.
      In frontotemporal dementia, tau is the major locus.
      • Poorkaj P
      • Bird TD
      • Wijsman E
      • et al.
      Tau is a candidate gene for chromosome 17 frontoiemporal dementia [published correction appears in Ann Neurol. 1998;44:428].
      • Hutton M
      • Lendon CL
      • Rizzu P
      • et al.
      Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17.
      Mutations in the prion gene underlie hereditary cases of prion disease.
      • Owen F
      • Poulter M
      • Lofthouse R
      • et al.
      Insertion in prion protein gene in familial Creutzfeldt-Jakob disease [letter].
      The cognate proteins of these pathogenic loci have direct relationships to the pathology of the relevant diseases; thus, APP and presenilin mutations influence APP processing such that more Aβ42 is produced,
      • Scheuner D
      • Eckman C
      • Jensen M
      • et al.
      Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin I and 2 and APP mutations linked to familial Alzheimer's disease.
      and this Aβ is a major component of the plaques that characterize Alzheimer disease.
      • Iwatsubo TR
      • Odaka A
      • Suzuki N
      • Mizusawa H
      • Nukina N
      • Jhara Y
      Visualization of Aβ42(43) and Aβ40 in senile plaques with end-specific Aβ monoclonals: evidence that an initially deposited species is Aβ42(43).
      α-Synuclein is a major component of the Lewy body of Parkinson disease.
      • Spillantini MG
      • Schmidt ML
      • Lee VM
      • Trojanowski JQ
      • Jakes R
      • Goedert M
      Alpha-synuclein in Lewy bodies [leller].
      The tau protein is the major component of neurofibrillary tangles and of the other unusual pathological features of frontotemporal dementias.
      • Spillantini MG
      • Bird TD
      • Ghetti B
      Frontotcmporal dementia and parkinsonism linked to chromosome 17: a new group of tauop-athies.
      Finally, many cases of prion disease have distinctive prion plaque deposits.
      • Taraboulos A
      • Jcndroska K
      • Serban D
      • Yang SL
      • DeArmond SJ
      • Prusiner SB
      Regional mapping of prion proteins in brain.
      Surprisingly, there are overlaps among the pathologies of these diseases (Table 1). Thus, tau-containing tangles are an almost invariant pathology in Alzheimer disease (strictly, they are necessary for establishing the diagnosis of Alzheimer disease), Lewy bodies are a frequent pathology in Alzheimer disease even in cases with APP mutations,
      • Lantos PL
      • Lulhert PJ
      • Hanger D
      • Anderton BH
      • Mullan M
      • Rossor M
      Familial Alzheimer's disease with the amyloid precursor protein position 717 mutation and sporadic Alzheimer's disease have the same cyloskeletal pathology.
      and both tangles and Lewy bodies are found in some cases of prion disease.
      • Dlouhy SR
      • Hsiao K
      • Farlow MR
      • et al.
      Linkage of the Indiana kindred of Gerslmann-Straussler-Scheinker disease to the prion protein gene.
      • Piccardo P
      • Mirra SS
      • Young K
      • Gearing M
      • Dlouhy SR
      • Ghetti B
      α-Synuclein accumulation in Gerstmann-Strausslcr-Schenker disease (GSS) with prion protein gene (PRNP) F198S.
      Despite this overlap, there appear to be clear hierarchies in these pathological findings. Thus, neither pronounced Aβ plaques nor prion deposits are found in diseases with mutations in the tau or α-synuclein genes, Lewy bodies have not been reported in cases with tau mutations, and tangles have not been seen in cases with α-synuclein gene mutations. Aβ plaques are not found (except incidentally in elderly patients) in cases with prion mutations, and prion deposits have not been found in cases with APP or PS mutations (except in extremely rare cases in which they are believed to reflect comorbidity).
      Table 1Relationship Between Diagnosis and Pathogenesis of Neurodegenerative Disease
      DiseaseUsual pathologyPrimary pathologic moleculeSecondary pathologic molecule
      Alzheimer diseaseNeuritic plaques and neurofibrillary tangles (Lewy bodies in only some cases)αβTau, a-synuclein (in only some cases)
      Priori diseasesPrion plaques in many cases; neurofibrillary tangles in only some casesPrPscTau, a-synuclein (both in only some cases)
      Parkinson diseaseLewy bodiesα-Synuclein
      Frontotemporal dementiasNeurofibrillary tangles or other abnormal tau pathologyTau
      This series of genetic and pathological findings can be organized into a pathogenic and diagnostic hierarchy (Figure 1). In this hierarchy, APP mismetabolism (Alzheimer disease) or abnormal prion biochemistry (prion disease) can lead to tau deposition as a secondary event; these diseases are secondary tauopathies. APP mismetabolism can lead to α-synuclein deposition (Alzheimer disease with Lewy bodies, a secondary synucleinopathy). Mutations in the tau or α-synuclein genes lead to primary tauopathies (frontotemporal dementia) and primary synucleinopathies (Parkinson disease), respectively. Undoubtedly, as more genetic loci are discovered, especially for Parkinson disease, this situation will become more complex. However, it seems as if the general rules previously outlined will hold. Thus, families with hereditary Lewy body parkinsonism encoded at loci other than α-synuclein always lack Aβ, tau, and prion pathology even in cases with dementia.
      • Muenter MD
      • Fomo LS
      • Hornykiewicz O
      • et al.
      Hereditary form of parkinsonism—dementia.
      Figure thumbnail gr1
      Fig. 1Proposed relationship among the various neurodegenerative diseases in terms of pathogenic pathways. The pathogenesis of 1 form of frontal temporal dementia, which is caused by mutations in the tau gene (FTDP-17),
      • Poorkaj P
      • Bird TD
      • Wijsman E
      • et al.
      Tau is a candidate gene for chromosome 17 frontoiemporal dementia [published correction appears in Ann Neurol. 1998;44:428].
      • Hutton M
      • Lendon CL
      • Rizzu P
      • et al.
      Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17.
      is shown in box I (orange) and box V (brown). The “typical” pathogenesis of Alzheimer disease is shown in box II (purple) and box V. However, Alzheimer disease frequently involves Lewy body pathology (box VI, blue). The pathogenesis of pure Lewy body diseases (including Parkinson disease) is shown in box III (green) and box VI. Besides mutations in the α-synuclein gene,
      • Polymeropoulos MH
      • Lavedan C
      • Leroy E
      • et al.
      Mutation in the alpha-synudcin gene identified in families with Parkinson's disease.
      loci leading to disease on chromosomes 2p’
      • Gasser T
      • Muller-Myhsok B
      • Wszolck ZK
      • et al.
      A susceptibility locus for Parkinson's disease maps to chromosome 2pl3.
      and 4p
      • Farrer M
      • Gwinn-Hardy K
      • Muenter M
      • et al.
      A chromosome 4p haplotype segregating with Parkinson's disease and postural tremor.
      have recently been reported. The pathogenesis of prion diseases is shown in box IV (gold): some cases of prion disease have tangles, Lewy bodies, or both, and thus these cases include boxes V and VI, respectively. APP = amyloid precursor protein.
      This idea of hierarchies of pathogenic processes is important and interesting for several reasons. It is interesting because it seems to point to an explanation for some of the neuronal selectivity of these diseases. For example, both the primary and the secondary tauopathies share clinical features. Although the Indiana prion disease kindred, Alzheimer disease, and frontotemporal dementias are clinically distinct, their clinical similarities are striking. Presumably, these similarities reflect neuronal susceptibilities to tau dysfunction. Thus, one could consider that the clinical features of “typical” Alzheimer disease reflect 2 sequential processes: first, the regional distribution of APP mismetabolism, and second, the regional selectivity to “tau-type” neurodegeneration. Similarly, α-synuclein pathology clearly has a predilection for certain cell groups, such as the substantia nigra, and this presumably underlies the parkinsonian features seen in cases of Alzheimer disease with Lewy bodies.
      Most clearly, these hierarchies are important because the pathologies observed in these diseases likely reflect common pathogenic biochemical processes. Thus, both Aβ and prions (under some circumstances) seem to activate a tau neurodegenerative process. Therefore, one would predict that treatment strategies that intervene in this process would be effective both in these diseases and in frontotemporal dementias. Similarly, strategies useful in the treatment of synuclein diseases may have some efficacy in certain cases of Alzheimer disease.
      Less certainly, these pathogenic hierarchies may enable us to draw clues across disease categories to try and understand disease pathogeneses. In addition, unusual and exceptional cases may shed a more general light on disease mechanisms. Thus, the clinical features of typical Alzheimer disease as well as the spastic paraparesis variant of Alzheimer disease
      • Crook R
      • Verkkoniemi A
      • Perez-Tur J
      • et al.
      A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1.
      and of the Indiana prion kindred
      • Ghetti B
      • Dlouhy SR
      • Giaccone G
      • et al.
      Gerstmann-Straussler-Scheinker disease and the Indiana kindred.
      are broadly similar, but the last 2 types lack neuritic plaques; this suggests that neuritic plaques are not on the major pathogenic route to cell damage, death, and dementia. Rather, the intracellular aggregation or dysfunction of insoluble, self-aggregating Aβ or prion peptides would seem to be 1 way of initiating the tau dysfunction. Similarly, some cases of frontotemporal dementias have typical neurofibrillary tangles (those with missense mutations), whereas others (those with splice site mutations) do not
      • Hutton M
      • Lendon CL
      • Rizzu P
      • et al.
      Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17.
      ; however, these variants have similar clinical features and patterns of neurodegeneration.
      • Hutton M
      • Lendon CL
      • Rizzu P
      • et al.
      Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17.
      • Spillantini MG
      • Bird TD
      • Ghetti B
      Frontotcmporal dementia and parkinsonism linked to chromosome 17: a new group of tauop-athies.
      This suggests that neurofibrillary tangles are not on the biochemical route to disease and that tau dysfunction is of greater pathological importance than tau deposition. Of course, the role of tau in microtubule stabilization is well known, and the major problem may be microtubule function, to which large cells are particularly vulnerable.
      These observations suggest that all these diseases form 2 related families: the tauopathies and the synucleinopathies; these diseases are related because Aβ can initiate both processes. In contrast, the triplet repeat diseases form another class,
      • Paulson HL
      • Fischbeck KH
      Trinucleotide repeats in neurogenetic disorders.
      and these also share clinical features with each other, although different primary genes are involved in each of these diseases. Minimal information is available concerning the route to cell death in the tauopathies, synucleinopathies, or triplet repeat diseases. However, a priori, it seems unlikely that these neurodegenerative processes have much in common with either classic necrotic or apoptotic cell death processes. The latter occur over minutes to hours, whereas the processes that lead to cell death in neurodegenerative diseases take place over months to years. Most likely, they involve subtle disregulation of homeostatic mechanisms. For example, the tauopathies may involve a chronic but slight dysfunction in the microtubule-dependent axonal transport in human neurons with long processes. Hopefully, the identification of the pathogenic loci and the production of transgenic mice, which model at least some of the disease process, will eventually facilitate the dissection of the pathways to cell death, as well as serve as models in which therapeutic strategies can be tested.

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