TY  - JOUR
A1  - Wulf, Maximilian
A1  - Barkovits, Katalin
A1  - Schork, Karin
A1  - Eisenacher, Martin
A1  - Riederer, Peter
A1  - Gerlach, Manfred
A1  - Eggers, Britta
A1  - Marcus, Katrin
T1  - The proteome of neuromelanin granules in dementia with Lewy bodies
JF  - Cells
N2  - Neuromelanin granules (NMGs) are organelle-like structures present in the human substantia nigra pars compacta. In addition to neuromelanin, NMGs contain proteins, lipids and metals. As NMG-containing dopaminergic neurons are preferentially lost in Parkinson’s disease and dementia with Lewy bodies (DLB), it is assumed that NMGs may play a role in neurodegenerative processes. Until now, this role is not completely understood and needs further investigation. We therefore set up an exploratory proteomic study to identify differences in the proteomic profile of NMGs from DLB patients (n = 5) compared to healthy controls (CTRL, n = 5). We applied a laser microdissection and mass-spectrometry-based approach, in which we used targeted mass spectrometric experiments for validation. In NMG-surrounding (SN\(_{Surr.}\)) tissue of DLB patients, we found evidence for ongoing oxidative damage and an impairment of protein degradation. As a potentially disease-related mechanism, we found α-synuclein and protein S100A9 to be enriched in NMGs of DLB cases, while the abundance of several ribosomal proteins was significantly decreased. As S100A9 is known to be able to enhance the formation of toxic α-synuclein fibrils, this finding points towards an involvement of NMGs in pathogenesis, however the exact role of NMGs as either neuroprotective or neurotoxic needs to be further investigated. Nevertheless, our study provides evidence for an impairment of protein degradation, ongoing oxidative damage and accumulation of potentially neurotoxic protein aggregates to be central mechanisms of neurodegeneration in DLB.
KW  - neuromelanin granules
KW  - neurodegeneration
KW  - dementia with Lewy bodies
KW  - proteomics
KW  - stress granules
KW  - substantia nigra pars compacta
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297465
SN  - 2073-4409
VL  - 11
IS  - 22
ER  - 
TY  - JOUR
A1  - Müller, Thomas
A1  - Mueller, Bernhard Klaus
A1  - Riederer, Peter
T1  - Perspective: Treatment for disease modification in chronic neurodegeneration
JF  - Cells
N2  - Symptomatic treatments are available for Parkinson's disease and Alzheimer's disease. An unmet need is cure or disease modification. This review discusses possible reasons for negative clinical study outcomes on disease modification following promising positive findings from experimental research. It scrutinizes current research paradigms for disease modification with antibodies against pathological protein enrichment, such as α-synuclein, amyloid or tau, based on post mortem findings. Instead a more uniform regenerative and reparative therapeutic approach for chronic neurodegenerative disease entities is proposed with stimulation of an endogenously existing repair system, which acts independent of specific disease mechanisms. The repulsive guidance molecule A pathway is involved in the regulation of peripheral and central neuronal restoration. Therapeutic antagonism of repulsive guidance molecule A reverses neurodegeneration according to experimental outcomes in numerous disease models in rodents and monkeys. Antibodies against repulsive guidance molecule A exist. First clinical studies in neurological conditions with an acute onset are under way. Future clinical trials with these antibodies should initially focus on well characterized uniform cohorts of patients. The efficiency of repulsive guidance molecule A antagonism and associated stimulation of neurogenesis should be demonstrated with objective assessment tools to counteract dilution of therapeutic effects by subjectivity and heterogeneity of chronic disease entities. Such a research concept will hopefully enhance clinical test strategies and improve the future therapeutic armamentarium for chronic neurodegeneration.
KW  - neurodegeneration
KW  - repulsive guidance molecule A
KW  - neuroprotection
KW  - repair
KW  - oxidative stress
KW  - apoptosis
KW  - neurogenesis
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236644
SN  - 2073-4409
VL  - 10
IS  - 4
ER  -