Formation and development of Lewy pathology: a critical update

Abstract

Filamentous protein inclusions in neurons (Lewy bodies, LB) and dystrophic neurites containing pathologic alpha-synuclein (alpha Syn) are the morphologic hallmarks of sporadic Parkinson disease (PD) and dementia with Lewy bodies (DLB), but are also found in aged subjects and in a variety of neurogenerative disorders. They occur in the central, peripheral, and autonomic nervous system as an essential or coincident feature. Their formation runs through several phases from initial dust-like particles cross-linked with alpha Syn to aggregation of ubiquitinated dense filaments, formation of LBs, finally degradation and death of the afflicted neurons. Pathologic accumulation of alpha Syn/LBs proposed by Braak et al. (Neurobiol Aging 24:197-211, 2003), following a predictable sequence of lesions in six stages with ascending progression from medullary and olfactory nuclei to the cortex, has been considered to be linked to clinical dysfunctions. The consensus pathologic guidelines of DLB (Neurology 65:1863-1872, 2005), by semiquantitative scoring to alpha Syn pathology (LB density and distribution) in specific brain regions, distinguish three phenotypes (brainstem, transitional/limbic, and diffuse neocortical), and also consider concomitant Alzheimer-related pathology. alpha Syn pathology in the amygdala is often associated with Alzheimer disease. Although some retrospective clinico-pathologic studies have largely confirmed the Braak LB staging system, it shows neither correlation to the clinical severity and duration of parkinsonism nor to nigral alpha Syn burden and cell loss which significantly correlates with resulting striatal loss of dopamine, dopamine transporter and tyrosine hydroxylase, duration and severity of motor dysfunction. Between 6.3 and 43% of clinically manifested PD cases did not follow this pattern, and in 7-8.3% of those with alpha Syn-positive inclusions in midbrain and cortex the medullary nuclei were spared. On the other hand, 30-55% of elderly subjects with widespread Lewy pathology revealed no neuropsychiatric symptoms or were not classifiable. Therefore, detection and staging of Lewy pathology without assessment of neuronal loss in specific areas may not have clinical impact and its predictive validity is questionable. For demented patients, modified criteria for categorization of Lewy pathology were proposed. If robust correlations between clinical course and Lewy/alpha Syn pathology are to be confirmed by future studies, the currently used morphologic staging/classification systems should be revised accordingly.

The role of α-synuclein in neurodegeneration — An update

“…Prions are composed solely of PrP Thus, the propagation of AS lesions by cellto-cell passage appears to be similar as that in other neurodegenerative disorders (see [9,626] [429][430][431]636]. The formation of axonal AS deposits and "pale bodies" [637] preceds the development of LBs in affected neurons.…”

“…Despite many similarities between DLB and PDD, several morphological differences have been demonstrated, in particular higher amyloid plaque load in striatum, usually absent in non-demented PD [37,38,630,708], and more severe AS load in hippocampal CA2/3 areas [429][430][431]. A recent study showed DLB cases having more severe Aβ load than PDD, but no differences in neuritic Braak and AS scores, while others found higher Aβ scores in cortical and subcortical areas [692].…”

Protein repertoire impact of Ubiquitin–Proteasome System impairment: Insight into the protective role of beta-estradiol

“…Although intracellular protein accumulation and aggregation are characteristics of many different neurological disorders the relationship between protein aggregates accumulation and pathogenesis has not been defined yet [39][40][41][42][43][44]. Indeed protein inclusions have been suggested to be toxic, protective or simply correlate with the disease without influencing its pathogenesis.…”

Anticipatory postural adjustments stabilise the whole upper-limb prior to a gentle index finger tap

“…Indeed, morphologic hallmarks of sporadic PD (Lewy bodies and dystrophic neurites containing pathologic α-synuclein) may appear initially in the lower brainstem [2]. However, Lewy pathology can correlate poorly with neuronal loss in specific areas, thus its validity in predicting neuronal disintegration is questionable [29]. In fact, noradrenergic neurons in the LC are relatively preserved in early PD and do not exhibit the same intracellular changes as in the substantia nigra [30].…”