Axonal degeneration as a therapeutic target in the CNS

Degeneration of the axon is an important step in the pathomechanism of traumatic, inflammatory and degenerative neurological diseases. Increasing evidence suggests that axonal degeneration occurs early in the course of these diseases and therefore represents a promising target for future therapeutic strategies. We review the evidence for axonal destruction from pathological findings and animal models with particular emphasis on neurodegenerative and neurotraumatic disorders. We discuss the basic morphological and temporal modalities of axonal degeneration (acute, chronic and focal axonal degeneration and Wallerian degeneration). Based on the mechanistic concepts, we then delineate in detail the major molecular mechanisms that underlie the degenerative cascade, such as calcium influx, axonal transport, protein aggregation and autophagy. We finally concentrate on putative therapeutic targets based on the mechanistic prerequisites

ROCKing Regeneration: Rho Kinase Inhibition as Molecular Target for Neurorestoration

Regenerative failure in the CNS largely depends on pronounced growth inhibitory signaling and reduced cellular survival after a lesion stimulus. One key mediator of growth inhibitory signaling is Rho-associated kinase (ROCK), which has been shown to modulate growth cone stability by regulation of actin dynamics. Recently, there is accumulating evidence the ROCK also plays a deleterious role for cellular survival. In this manuscript we illustrate that ROCK is involved in a variety of intracellular signaling pathways that comprise far more than those involved in neurite growth inhibition alone. Although ROCK function is currently studied in many different disease contexts, our review focuses on neurorestorative approaches in the CNS, especially in models of neurotrauma. Promising strategies to target ROCK by pharmacological small molecule inhibitors and RNAi approaches are evaluated for their outcome on regenerative growth and cellular protection both in preclinical and in clinical studies

Septic embolic encephalitis after Staphylococcus aureus endocarditis of a prosthetic valve in a 57-year-old woman: a case report

For prosthetic heart valves the risk of infection is much higher than for native heart valves. During the course of infective endocarditis 20-40% of all patients suffer from cerebrovascular complications such as ischaemic stroke or intracerebral haemorrhage. We present the case of a 57-year-old woman who had undergone surgery to mechanically replace an aortic heart valve 11 months ago and suffered from repeated ischaemic strokes with secondary haemorrhage. The initial antibiotic regimen was ineffective in treating the later diagnosed Staphylococcus aureus infection of the prosthetic valve. Escalation of the antibiotic treatment was not able to halt the clinical course that finally led to the patient’s death. The case report emphasizes the importance of early identification of the aetiology of infection in patients with mechanical heart valve replacement. Without rapid and adequate treatment there is a considerable risk for the development of severe neurological sequelae and cardiac failure that can ultimately result in a fatal course of this clinical picture

Brainstem Raphe Alterations in TCS: A Biomarker for Depression and Apathy in Parkinson's Disease Patients

Depression and apathy can both be present in patients with Parkinson's disease (PD) while e. g., essential tremor (ET) patients mostly only report depressive symptoms. In PD, depression has been linked with brainstem raphe (BR) signal alterations in transcranial sonography (TCS) but apathy has not been evaluated in such terms as a putative biomarker. Furthermore, the BR has only been investigated using a singular axial TCS examination plane, although coronal TCS examination allows a much more accurate evaluation of the craniocaudal formation of serotonergic raphe structures in the midbrain area. The objective of this study was to investigate the value of coronal TCS examination for the detection of BR signal alterations and clinically correlate it to apathy in patients with PD, ET and healthy controls (HC). We prospectively included PD patients (n = 31), ET patients (n = 16), and HC (n = 16). All were examined by TCS in the axial and coronal plane with focus on BR signal alterations. LARS and BDI-II scores were conducted to assess apathic and depressive symptoms in the study population. In a detailed analysis we found that the correlation of coronal and axial TCS alterations of BR was very high (rho = 0.950, p < 0.001). BR signal alterations were more frequent in PD patients than in ET patients and HC, while it was not different between ET patients and HC. In the PD patient group, BDI-II and LARS scores were negatively correlated to BR signal changes in TCS in a significant manner (BDI-II and axial BR: p = 0.019; BDI-II and coronal BR: p = 0.011; LARS and axial BR: p = 0.017; LARS and coronal BR: p = 0.023). Together in this brainstem ultrasound study we find a significant association of BR signal alterations with clinically evident apathy and depression in patients with PD. Therefore, TCS might enable the identification of a subgroup of PD patients which are at higher risk to suffer from or to develop depression or apathy

Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, yet disease-modifying treatments do not currently exist. Rho-associated protein kinase (ROCK) was recently described as a novel neuroprotective target in PD. Since alpha-synuclein (alpha-Syn) aggregation is a major hallmark in the pathogenesis of PD, we aimed to evaluate the anti-aggregative potential of pharmacological ROCK inhibition using the isoquinoline derivative Fasudil, a small molecule inhibitor already approved for clinical use in humans. Fasudil treatment significantly reduced alpha-Syn aggregation in vitro in a H4 cell culture model as well as in a cell-free assay. Nuclear magnetic resonance spectroscopy analysis revealed a direct binding of Fasudil to tyrosine residues Y133 and Y136 in the C-terminal region of alpha-Syn. Importantly, this binding was shown to be biologically relevant using site-directed mutagenesis of these residues in the cell culture model. Furthermore, we evaluated the impact of long-term Fasudil treatment on alpha-Syn pathology in vivo in a transgenic mouse model overexpressing human alpha-Syn bearing the A53T mutation (alpha-Syn(A53T) mice). Fasudil treatment improved motor and cognitive functions in alpha-Syn(A53T) mice as determined by Catwalk (TM) gait analysis and novel object recognition (NOR), without apparent side effects. Finally, immunohistochemical analysis revealed a significant reduction of alpha-Syn pathology in the midbrain of alpha-Syn(A53T) mice after Fasudil treatment. Our results demonstrate that Fasudil, next to its effects mediated by ROCK-inhibition, directly interacts with alpha-Syn and attenuates alpha-Syn pathology. This underscores the translational potential of Fasudil as a disease-modifying drug for the treatment of PD and other synucleinopathies

Recommendations for Standards of Network Care for Patients with Parkinson’s Disease in Germany

Although our understanding of Parkinson’s disease (PD) has improved and effective treatments are available, caring for people with PD remains a challenge. The large heterogeneity in terms of motor symptoms, nonmotor symptoms, and disease progression makes tailored individual therapy and individual timing of treatment necessary. On the other hand, only limited resources are available for a growing number of patients, and the high quality of treatment cannot be guaranteed across the board. At this point, networks can help to make better use of resources and improve care. The working group PD Networks and Integrated Care, part of the German Parkinson Society, is entrusted to convene clinicians, therapists, nurses, researchers, and patients to promote the development of PD networks. This article summarizes the work carried out by the working group PD Networks and Integrated Care in the development of standards of network care for patients with PD in Germany

Calpain-mediated cleavage of collapsin response mediator protein-2 drives acute axonal degeneration

Axonal degeneration is a key initiating event in many neurological diseases. Focal lesions to axons result in a rapid disintegration of the perilesional axon by acute axonal degeneration (AAD) within several hours. However, the underlying molecular mechanisms of AAD are only incompletely understood. Here, we studied AAD in vivo through live-imaging of the rat optic nerve and in vitro in primary rat cortical neurons in microfluidic chambers. We found that calpain is activated early during AAD of the optic nerve and that calpain inhibition completely inhibits axonal fragmentation on the proximal side of the crush while it attenuates AAD on the distal side. A screening of calpain targets revealed that collapsin response mediator protein-2 (CRMP2) is a main downstream target of calpain activation in AAD. CRMP2-overexpression delayed bulb formation and rescued impairment of axonal mitochondrial transport after axotomy in vitro. In vivo, CRMP2-overexpression effectively protected the proximal axon from fragmentation within 6 hours after crush. Finally, a proteomic analysis of the optic nerve was performed at 6 hours after crush, which identified further proteins regulated during AAD, including several interactors of CRMP2. These findings reveal CRMP2 as an important mediator of AAD and define it as a putative therapeutic target

miR-182-5p and miR-183-5p Act as GDNF Mimics in Dopaminergic Midbrain Neurons.

Parkinson’s disease (PD) is the second-most-frequent neurodegenerative disorder worldwide. One major hallmark of PD is the degeneration of dopaminergic (DA) neurons in the substantia nigra. Glial cell line-derived neurotrophic factor (GDNF) potently increases DA neuron survival in models of PD; however, the underlying mechanisms are incompletely understood. MicroRNAs (miRNAs) are small, non-coding RNAs that are important for post-transcriptional regulation of gene expression. Using small RNA sequencing, we show that GDNF specifically increases the expression of miR-182-5p and miR-183-5p in primary midbrain neurons (PMNs). Transfection of synthetic miR-182-5p and miR-183-5p mimics leads to increased neurite outgrowth and mediates neuroprotection of DA neurons in vitro and in vivo, mimicking GDNF effects. This is accompanied by decreased expression of FOXO3 and FOXO1 transcription factors and increased PI3K-Akt signaling. Inhibition of endogenous miR-182-5p or miR-183-5p in GDNF-treated PMNs attenuated the pro-DA effects of GDNF. These findings unveil an unknown miR-mediated mechanism of GDNF action and suggest that targeting miRNAs is a new therapeutic avenue to PD phenotypes

JNK Isoforms Differentially Regulate Neurite Growth and Regeneration in Dopaminergic Neurons In Vitro

Parkinson’s disease is characterized by selective and progressive loss of midbrain DAergic neurons (MDN) in the substantia nigra and degeneration of its nigrostriatal projections. Whereas the cellular pathophysiology has been closely linked to an activation of c-Jun N-terminal kinases (JNKs) and c-Jun, the involvement of JNKs in regenerative processes of the nigrostriatal pathway is controversially discussed. In our study, we utilized a mechanical scratch lesion paradigm of midbrain DAergic neurons in vitro and studied regenerative neuritic outgrowth. After a siRNA-mediated knockdown of each of the three JNK isoforms, we found that JNKs differentially regulate neurite regeneration. Knockdown of JNK3 resulted in the most prominent neurite outgrowth impairment. This effect was attenuated again by plasmid overexpression of JNK3. We also evaluated cell survival of the affected neurons at the scratch border. JNK3 was found to be also relevant for survival of MDN which were lesioned by the scratch. Our data suggest that JNK isoforms are involved in differential regulation of cell death and regeneration in MDN depending on their neurite integrity. JNK3 appears to be required for regeneration and survival in the case of an environment permissive for regeneration. Future therapeutic approaches for the DAergic system may thus require isoform specific targeting of these kinases