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Volume 3

Parkinson’s 2019

November 11-12, 2019

Page 14

Parkinson’s & Movement Disorders

November 11-12, 2019 | London, UK

7

th

International Conference on

Journal of Neurology and Clinical Neuroscience

J Neurol Clin Neurosci . | Volume 3

Iria Carballo-Carbajal

Vall d’Hebron Research Institute, Spain

Role of Neuromelanin in Parkinson’s disease

Statement of the Problem:

In Parkinson’s disease (PD), there is a preferential degeneration of melanin-containing

neurons, in particular dopaminergic neurons of the substantia nigra (SN). Loss of nigral neurons results in the typical

motor symptoms of the disease, which constitute the cardinal clinical diagnostic criterion for PD. However, the

potential contribution of neuromelanin to PD pathogenesis remain elusive because, in contrast to humans, common

laboratory animals, such as rodents, lack neuromelanin.

Methodology & Theoretical Orientation:

Unilateral vector-mediated expression in rat of human tyrosinase

(hTyr), rate-limiting enzyme for the synthesis of peripheral melanins, resulted in an age-dependent production of

neuromelanin within nigral dopaminergic neurons. Neuromelanin levels in rat where comparable to those reached

in elderly humans, allowing for the first time to assess

in vivo

the consequences of progressive neuromelanin

accumulation.

Findings:

Accumulation of neuromelanin above a specific threshold ultimately compromised neuronal function and

led to an age-dependent PD phenotype comprising nigrostriatal neurodegeneration, hypokinesia, impaired dopamine

release and Lewy body-like inclusion formation. In humans, both PD patients and pre-symptomatic subjects reached

this pathogenic threshold of intracellular melanin, in contrast to control healthy brains. At the molecular level,

decreases in both autophagic and ubiquitin-proteasome degradation system activities pointed to a general failure of

cellular proteostasis. Indeed, enhancement of lysosomal proteostasis by overexpressing the transcription factor EB

(TFEB) reduced neuromelanin levels and prevented neurodegeneration in tyrosinase-expressing animals.

Conclusion & Significance:

Our results reveal a novel pathogenic scenario in PD, in which the continuous, age-

dependent build-up of neuromelanin within autophagic compartments may ultimately exhaust the vesicular storage

capacity of the cell when reaching a certain threshold of accumulation, imparting general proteostasis in the cell.

Modulation of neuromelanin accumulation may thus provide unprecedented therapeutic opportunities for PD and

brain aging.

Biography

Iria Carballo-Carbajal has long expertise in studying the cellular mechanisms underlying neurodegeneration in Parkinson’s disease (PD).

In the last years, she has extensively investigated the molecular bases involved in LRRK2-associated pathogenesis as well as in the

regulation and pathological spreading of alpha-synuclein using different cell-based, iPSC-derived and

in vivo

animal models. Her current

research interest focuses on the potential role of neuromelanin in PD. A major contribution has been the generation of the first

in vivo

model of melanized

substantia nigra

in rodents, showing that progressive accumulation of this dark pigment with age can finally lead

to a parkinsonian phenotype, which reproduces main motor, functional and neuropathological features observed in patients. These re-

sults, recently published in Nature Communications, may open the door to new therapeutic avenues and to a paradigm shift in the field.

iria.carballo.carbajal@gmail.com