PD is associated with protein accumulation and aggregation, mitochondrial abnormalities, and neuronal loss in the substantia nigra and elsewhere in the brain. Based on the genetics of PD, it appears that abnormal protein and organelle clearance due to defects in autophagy and lysosomal degradation have a pathogenic role in the disease. One clue and diagnostic feature of the disease is the Lewy body, a characteristic inclusion containing α-synuclein, a protein involved in synaptic transmission. While PD in most cases is sporadic, point mutations and duplications of the gene encoding α-synuclein cause autosomal dominant PD. Synuclein aggregates are cleared by autophagy (Chapter 2), and several mutations associated with PD are in genes whose products (LRRK2, Parkin, others) all appear to have roles in endosomal trafficking pathways implicated in autophagy. It also has been demonstrated that heterozygosity for the Gaucher disease–causing mutation in glucocerebrosidase is a risk factor for PD. Glucocerebrosidase is a lysosomal enzyme, yet another clue suggesting that abnormal turnover of cellular constituents somehow sets the stage for the development of PD.
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Fig. 23.26 Frontotemporallobardegeneration(FTLD).(A)Atrophyofthetemporalcortexcanbeseenincomparisontotherelativepreservationoffrontalcortex.(B)Severeneuronallossandgliosisintheregionofatrophy.(C)FTLD-tau.CytoplasmicinclusionscontainingTDP43areseeninassociationwithlossofnormalnuclearimmunoreactivity.(D)FTLD-TDP.SomeformsofFTLDareassociatedwithneuronalintranuclearinclusionscontainingTDP43.
Fig.23.27A–B )andlocusceruleus.Microscopicfeaturesincludelossofthepigmented,catecholaminergicneuronsintheseregionsassociatedwithgliosis.Lewy bodies (see
Fig.23.27C )maybefoundinthoseneuronsthatremain.Thesearesingleormultiple,cytoplasmic,eosinophilic,roundtoelongatedinclusions.Onultrastructuralexamination,Lewybodiesconsistoffinefilaments,composedofα-synucleinandotherproteins,includingneurofilamentsandubiquitin.TheothermajorhistologicfindingisthepresenceofLewy neurites, dystrophicneuritesthatalsocontainaggregatedα-synuclein.Immunohistochemicalstainingforα-synucleinhighlightsmoresubtleLewybodiesandLewyneuritesinmanybrainregionsoutsideofthesubstantianigraandinnon-dopaminergicneurons,includingregionsofthemedulla,thepons,theamygdala,andthecerebralcortex.Eventuallytheyappearinthesubcorticalareasandthecerebralcortex.Withinvolvementofthecerebralcortex,thereistypicallydementiapresentinadditiontothemovementdisorder.
Fig. 23.27 Parkinsondisease.(A)Normalsubstantianigra.(B)DepigmentedsubstantianigrainidiopathicParkinsondisease.(C)Lewybodyinaneuronfromthesubstantianigrastainspink.
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PD commonly manifests as a movement disorder in the absence of a toxic exposure or other known underlying etiology. The disease usually progresses over 10 to 15 years, eventually producing severe motor slowing to the point of near immobility. Death usually is the result of aspiration pneumonia or trauma from falls caused by postural instability.