Determinants of selective neuronal vulnerability in Parkinson's disease

Parkinson´s disease (PD) is the second most frequent neurodegenerative disease affecting the population older than 65 years old. This incidence will greatly increase due to the progressive aging of the population in the coming years. PD diagnosis is made when there is a 50-60% dopaminergic cell loss in the substantia nigra pars compacta (SNc) and the striatal dopamine loss reaches around 70-80%, coinciding with the onset of classical parkinsonian motor signs: tremor, rigidity and slowness of movement. A significant proportion of patients present non-motor symptoms, generally associated to disfunction of non-dopaminergic regions, which can appear before, around or after diagnosis (10-15 years). Therefore, in PD both dopaminergic and non-dopaminergic groups are affected, but the motor manifestations are the main reason for consultation and causes the greatest disability for many years. There is a large heterogeneity within dopaminergic neural groups in terms of morphology, metabolism, molecular pattern, protein accumulation, inflammation levels, protein expression, etc. In this review we discuss different factors that could explain the special vulnerability of certain dopaminergic neurons in the SNc. Knowledge on the mechanisms and underlying factors of this selective vulnerability of the ventrolateral dopaminergic neuros of the SNc is essential for developing neuromodulatory and/or neuroprotective therapies, leading in turn to halt or modify the neurodegenerative process in PD.

Complicity of α-synuclein oligomer and calcium dyshomeostasis in selective neuronal vulnerability in Lewy body disease

Abstractα-Synuclein oligomers and Ca2+ dyshomeostasis have been thoroughly investigated with respect to the pathogenesis of Lewy body disease (LBD). In LBD, α-synuclein oligomers exhibit a neuron-specific cytoplasmic distribution. Highly active neurons and neurons with a high Ca2+ burden are prone to damage in LBD. The neuronal vulnerability may be determined by transneuronal axonal transmission of the pathological processes; however, this hypothesis seems inconsistent with pathological findings that neurons anatomically connected to LBD-vulnerable neurons, such as neurons in the ventral tegmentum, are spared in LBD. This review focuses on and discusses the crucial roles played by α-synuclein oligomers and Ca2+ dyshomeostasis in early intraneural pathophysiology in LBD-vulnerable neurons. A challenging view is proposed on the synergy between retrograde transport of α-synuclein and vesicular Ca release, whereby neuronal vulnerability is propagated backward along repeatedly activated signaling pathway.

Multi-phaseted problems of TDP-43 in selective neuronal vulnerability in ALS

Transactive response DNA-binding protein 43 kDa (TDP-43) encoded by the TARDBP gene is an evolutionarily conserved heterogeneous nuclear ribonucleoprotein (hnRNP) that regulates multiple steps of RNA metabolism, and its cytoplasmic aggregation characterizes degenerating motor neurons in amyotrophic lateral sclerosis (ALS). In most ALS cases, cytoplasmic TDP-43 aggregation occurs in the absence of mutations in the coding sequence of TARDBP. Thus, a major challenge in ALS research is to understand the nature of pathological changes occurring in wild-type TDP-43 and to explore upstream events in intracellular and extracellular milieu that promote the pathological transition of TDP-43. Despite the inherent obstacles to analyzing TDP-43 dynamics in in vivo motor neurons due to their anatomical complexity and inaccessibility, recent studies using cellular and animal models have provided important mechanistic insights into potential links between TDP-43 and motor neuron vulnerability in ALS. This review is intended to provide an overview of the current literature on the function and regulation of TDP-43-containing RNP granules or membraneless organelles, as revealed by various models, and to discuss the potential mechanisms by which TDP-43 can cause selective vulnerability of motor neurons in ALS.