Search

Pain is a distressing non-motor symptom experienced by up to 85% of people with Parkinson’s disease (PD), yet it is often untreated. This pain is likely to be influenced by many factors, including the disease process, PD impairments as well as co-existing musculoskeletal and/or neuropathic pain conditions. Expert opinion recommends that exercise is included as one component of pain management programs; however, the effect of exercise on pain in this population is unclear. This review presents evidence describing the potential influence of exercise on the pain-related pathophysiological processes present in PD. Emerging evidence from both animal and human studies suggests that exercise might contribute to neuroplasticity and neuro-restoration by increasing brain neurotrophic factors, synaptic strength and angiogenesis, as well as stimulating neurogenesis and improving metabolism and the immune response. These changes may be beneficial in improving the central processing of pain. There is also evidence that exercise can activate both the dopaminergic and non-dopaminergic pain inhibitory pathways, suggesting that exercise may help to modulate the experience of pain in PD. Whilst clinical data on the effects of exercise for pain relief in people with PD are scarce, and are urgently needed, preliminary guidelines are presented for exercise prescription for the management of central neuropathic, peripheral neuropathic and musculoskeletal pain in PD.

Podosomes are highly dynamic structures that are involved in cell adhesion and extracellular matrix remodeling. They present as intracellular columns composed of an actin-rich core region and a surrounding ring-like structure containing focal adhesion proteins, actin binders as well as cell signaling molecules. A key player in podosome biogenesis is the scaffolding protein cortactin, which is thought to control actin assembly at the core region. We show that the zona occludens protein 1 (ZO-1), a pivotal tight junction protein and known binding partner of cortactin, is a component of podosomes. In the smooth muscle cell line A7r5, phorbol ester treatment induced a rapid relocation of ZO-1 from the cell cortex and cytosolic pools toward newly formed podosomes. Podosomal localization was also observed for the known ZO-1-binding proteins l-afadin, α-catenin, and phospho-connexin 43. Truncation studies revealed that the actin-binding domain but not the association with cortactin is necessary for ZO-1 recruitment to podosomes. Moreover, impaired ZO-1 expression leads to significantly reduced podosome formation and concomitant decreased matrix degradation at podosomes. Our findings demonstrate that besides their known function in tight junction assembly and intercellular communication, zona occludens proteins and their binding partners may play a novel role in podosome formation and associated function, thus regulating cell adhesion and matrix remodeling.

The human endothelium forms a permeable barrier between the blood stream and surrounding tissue, strictly governing the passage of immune cells and metabolites. Regulation of cell-cell contact dynamics between endothelial cells is essential for the maintenance of its function and the vascular integrity. Besides other junctional systems, the accurate adhesion of cells is mainly dependent on the adherens junctions system, which is predominantly composed of intercellular adhesion proteins such as VE-cadherin and nectin, as well as their associated proteins. Drebrin, a protein mainly expressed in neurons, has been included in the growing list of “junction associated” proteins, but its exact role in adherens junction dynamics has so far been unclear. In this study, we show that knockdown of drebrin leads to functional impairments of endothelial monolayers, as demonstrated by a decrease of transendothelial electrical resistance (TER) and rupturing of HUVEC monolayers cultured under constant unidirectional flow conditions. The observed weakening of cell-cell contacts upon drebrin depletion is characterized by a specific and complete loss of nectin from adherens junctions, due to its endocytosis and subsequent degradation in lysosomes. The importance of drebrin for nectin’s presence at junctions is underlined by rescue experiments, where transient re expression of siRNA-insensitive drebrin stabilizes nectin at the junctional area. To support the fact that the phenotype is indeed due to loss of nectin, we established a knockdown of all endothelial nectin isoforms, which resulted in an even more pronounced phenotype than drebrin knockdown. Conducting co-immunoprecipitation experiments, we could show that drebrin does not interact with nectin directly but with its most prominent intracellular binding partner, afadin. Direct binding of drebrin and afadin is mediated through their polyproline and PR1-2 regions as shown by GST pulldown experiments using bacterially expressed domain constructs of both proteins. Concomitantly, confocal microscopy studies revealed strong binding between the two proteins on a subcellular level: drebrin’s polyproline region fused to a mitochondrial targeting signal is sufficient to relocalize afadin towards the outer membrane of mitochondria. Due to its association with nectin, afadin is also affected by drebrin knockdown – its mobility at the junctional area is enhanced, as shown by FRAP experiments, even though it still localizes to junctions, probably through binding other proteins, such as ZO-1 or α-catenin. Furthermore, we could demonstrate that drebrin maintains junctional integrity through its ability to link the nectin/afadin system to the cortical F-actin network. Being equipped with an F-actin binding module (CC-region) and the afadin-binding polyproline region, it anchors afadin to F-actin. Simultaneously, afadin binds to nectin through its PDZ region, resulting in a chain of protein interactions: F-actin-drebrin-afadin-nectin, which indirectly stabilizes nectin at the F-actin network (Figure 46A). Evidence, verifying that linkage of nectin to F actin is essential for monolayer integrity is provided by rescue of junctional nectin, under knockdown of both drebrin and afadin, through overexpression of minimal constructs containing exclusively afadin´s PDZ region coupled to drebrin´s F-actin binding region, or lifeact (Figure 46C). Drebrin, containing binding sites for both afadin and F-actin, is thus uniquely equipped to stabilize nectin at endothelial junctions, thereby preserving endothelial integrity. Altogether, these results contribute to the current understanding of how junctions are regulated in the endothelium under vascular flow, especially elucidating the significance of nectins. In particular, the newly identified interaction between drebrin and afadin, which establishes the necessary linkage of nectins to cortical F-actin, is shown to be crucial for junctional integrity.

Coronin 1C (synonyms: coronin-3, CRN2), a WD40 repeat-containing protein involved in cellular actin dynamics, is ubiquitously expressed in human tissues. Here, we report on the identification and functional characterization of two novel coronin 1C isoforms, referred to as CRN2i2 and CRN2i3, which also associate with F-actin. Analyses of the coronin 1C gene disclosed a single promoter containing binding sites for myogenic regulatory factors and an alternative first exon 1b present in intron 1, which give rise to the novel isoforms. Chromatin immunoprecipitation studies demonstrate MyoD binding to a region of the CRN2 gene, which contains a highly conserved E-box element in exon 1a. Gel-filtration assays suggest that the largest isoform 3 exists as a monomer, in contrast to isoform 1 and isoform 2 appearing as trimers. CRN2i3, which can be induced by MyoD, is exclusively expressed in well-differentiated myoblasts as well as in mature skeletal muscle tissue. In human skeletal muscle, CRN2i3 is a novel component of postsynaptic neuromuscular junctions and thin filaments of myofibrils. Together, our findings postulate a role for CRN2 isoforms in the structural and functional organization of F-actin in highly ordered protein complexes.