Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options

Abstract

Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.

Figure 1

Sketch of the putative pathophysiology underlying tauopathies of various etiologies. The physiologic role of tau as a stabilizer of neuronal microtubules by binding to microtubules can be disrupted through a multitude of insults (raised intracellular calcium levels, energy depletion, Aβ, etc), resulting in a hyperphosphorylation of tau at specific sites. Hyperphosphorylation of tau leads to altered binding of tau to neuronal microtubules, causing a destabilization of microtubule dynamics, such as the disintegration of microtubules, resulting in a disruption of microtubule-motor protein (dynactin–dynein complex, kinesin complex) interactions. This dysfunction of cytoskeletal properties may lead to a misdistribution of microtubule-associated cell components, e.g. mitochondria. In addition, tau fragments generated through proteolytic processes result in presumably toxic truncated tau species, e.g. displaying a reduced degradability. Finally, tau proteins or fragments of tau detached from microtubules may form filamentous aggregates (neurofibrillary tangles) through various intermediate confirmations and a seeding process (nucleation).