Perceived Exercise Habits of Individuals with Parkinson’s Disease Living in the Community

Context Exercise has been shown to improve gait in individuals with Parkinson’s disease (PD). Stepping practice at higher intensity levels has been suggested as a beneficial treatment option to improve gait in the neurological population. Unfortunately, this mode is poorly understood and underutilized within the PD population. Information on what individuals with PD are doing for exercise would be beneficial to help tailor exercise programs to improve gait and provide exercise options in the community for intensity-based exercise. Objective To investigate the current exercise habits of individuals living with PD in the community aimed at improving walking and to understand the impact of perceived intensity on daily exercise practices. Design, setting, participants One hundred thirty-eight individuals with PD living in the community were surveyed online regarding their current exercise habits. Main outcome measure A total of 22 questions aimed to understand exercise selection, focus, and perceived intensity. Questions asked basic demographic, symptom presentation and management of disease related symptoms that were present while living with PD. Exercise questions focused understanding participants current function level, practice exercise habits and perceived levels of exercise intensity during daily routines. Results Of the 138 individuals surveyed for this preliminary study, eighty-seven percent of individuals with PD participated in exercise with seventy-five percent choosing walking as a mode for exercise. Sixty-five percent of the respondents noted that despite exercise, their walking speed and endurance has worsened since diagnosis. Eighty-one percent perceived exercising at moderate intensity levels, however little provocation of intensity symptoms was noted. Conclusion Our preliminary study survey results suggest that individuals with PD are exercising but not at high enough intensity levels to promote improvements in gait performance. Individuals with PD may need to be pushed at higher intensity levels, beyond their voluntary limits, to induce gait performance changes. These findings can provide a foundation for future fitness interventions within this population to target improving gait

Type-Specific inositol 1,4,5-Trisphosphate Receptor Localization in the Vomeronasal Organ and its interaction with a Transient Receptor Potential Channel, TRPC2

The vomeronasal organ (VNO) is the receptor portion of the accessory olfactory system and transduces chemical cues that identify social hierarchy, reproductive status, conspecifics and prey. Signal transduction in VNO neurons is apparently accomplished via an inositol 1,4,5-trisphosphate (IP3)-activated calcium conductance that includes a different set of G proteins than those identified in vertebrate olfactory sensory neurons. We used immunohistochemical (IHC) and SDS-PAGE/western analysis to localize three IP3 receptors (IP3R) in the rat VNO epithelium. Type-I IP3R expression was weak or absent. Antisera for type-II and -III IP3R recognized appropriate molecular weight proteins by SDS-PAGE, and labeled protein could be abolished by pre-adsorption of the respective antibody with antigenic peptide. In tissue sections, type-II IP3R immunoreactivity was present in the supporting cell zone but not in the sensory cell zone. Type-III IP3R immunoreactivity was present throughout the sensory zone and overlapped that of transient receptor potential channel 2 (TRPC2) in the microvillar layer of sensory epithelium. Co-immunoprecipitation of type-III IP3R and TRPC2 from VNO lysates confirmed the overlapping immunoreactivity patterns. The protein-protein interaction complex between type-III IP3R and TRPC2 could initiate calcium signaling leading to electrical signal production in VNO neurons

Constitutive recycling of the store-operated Ca2+ channel Orai1 and its internalization during meiosis

Orai1 trafficking between the cell membrane and endosomes during meiosis requires caveolin and is important for tuning calcium signaling during oocyte maturation

Enantioselective Protein-Sterol Interactions Mediate Regulation of Both Prokaryotic and Eukaryotic Inward Rectifier K+ Channels by Cholesterol

Cholesterol is the major sterol component of all mammalian cell plasma membranes and plays a critical role in cell function and growth. Previous studies have shown that cholesterol inhibits inward rectifier K+ (Kir) channels, but have not distinguished whether this is due directly to protein-sterol interactions or indirectly to changes in the physical properties of the lipid bilayer. Using purified bacterial and eukaryotic Kir channels reconstituted into liposomes of controlled lipid composition, we demonstrate by 86Rb+ influx assays that bacterial Kir channels (KirBac1.1 and KirBac3.1) and human Kir2.1 are all inhibited by cholesterol, most likely by locking the channels into prolonged closed states, whereas the enantiomer, ent-cholesterol, does not inhibit these channels. These data indicate that cholesterol regulates Kir channels through direct protein-sterol interactions likely taking advantage of an evolutionarily conserved binding pocket

Ion channel clustering enhances weak electric field detection by neutrophils: apparent roles of SKF96365-sensitive cation channels and myeloperoxidase trafficking in cellular responses

We have tested Galvanovskis and Sandblom’s prediction that ion channel clustering enhances weak electric field detection by cells as well as how the elicited signals couple to metabolic alterations. Electric field application was timed to coincide with certain known intracellular chemical oscillators (phase-matched conditions). Polarized, but not spherical, neutrophils labeled with anti-K v 1.3, FL-DHP, and anti-TRP1, but not anti-T-type Ca 2+ channels, displayed clusters at the lamellipodium. Resonance energy transfer experiments showed that these channel pairs were in close proximity. Dose-field sensitivity studies of channel blockers suggested that K + and Ca 2+ channels participate in field detection, as judged by enhanced oscillatory NAD(P)H amplitudes. Further studies suggested that K + channel blockers act by reducing the neutrophil’s membrane potential. Mibefradil and SKF93635, which block T-type Ca 2+ channels and SOCs, respectively, affected field detection at appropriate doses. Microfluorometry and high-speed imaging of indo-1-labeled neutrophils was used to examine Ca 2+ signaling. Electric fields enhanced Ca 2+ spike amplitude and triggered formation of a second traveling Ca 2+ wave. Mibefradil blocked Ca 2+ spikes and waves. Although 10 μM SKF96365 mimicked mibefradil, 7 μM SKF96365 specifically inhibited electric field-induced Ca 2+ signals, suggesting that one SKF96365-senstive site is influenced by electric fields. Although cells remained morphologically polarized, ion channel clusters at the lamellipodium and electric field sensitivity were inhibited by methyl-β-cyclodextrin. As a result of phase-matched electric field application in the presence of ion channel clusters, myeloperoxidase (MPO) was found to traffic to the cell surface. As MPO participates in high amplitude metabolic oscillations, this suggests a link between the signaling apparatus and metabolic changes. Furthermore, electric field effects could be blocked by MPO inhibition or removal while certain electric field effects were mimicked by the addition of MPO to untreated cells. Therefore, channel clustering plays an important role in electric field detection and downstream responses of morphologically polarized neutrophils. In addition to providing new mechanistic insights concerning electric field interactions with cells, our work suggests novel methods to remotely manipulate physiological pathways.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46726/1/249_2005_Article_1.pd

CHANGING THE PERSPECTIVE IN MANAGEMENT OF A PROGRESSIVE NEUROLOGICAL DISORDER: DEVELOPING INTERVENTIONS TO TARGET MULTIFACTORIAL COMPONENTS OF PARKINSON’S DISEASE WITH EMPHASIS ON IMPROVING CLINICAL MEANINGFUL OUTCOMES

Neurological disorders are currently the leading source of disability in the United States with Parkinson’s disease (PD) having the fastest growing incidence rate (Abate et al., 2017). PD is the second most common degenerative disease in older adults above 60 years old (Tysnes & Storstein, 2017) and epidemiology reports predict that the number of PD cases has doubled to 6 million since 1990 (Dorsey, Sherer, et al., 2018) It is estimated that PD prevalence will continue to rise with a projected 60,000 new cases in the United States by 2030 (Dorsey, Elbaz, et al., 2018) and has the potential to reach more than 12 million cases worldwide by 2040 (Dorsey, Sherer, et al., 2018). PD is an incurable, progressive neurological disorder, that presents with both motor and non-motor symptoms that effects one’s functional mobility potential. The multifactor impact of PD, including both motor and non-motor features, has a negative effect on functional mobility potential for individuals living with PD. Walking, a component of functional mobility, becomes more difficult as the disease progresses. A once previously learned automated task, is compromised secondary to a variety of motor deficits. In addition, non-motor symptoms can worsen motor complications, gait difficulties, disability, and self-perceived health status (Dissanayaka et al., 2010; Pontone et al., 2009; Yamanishi et al., 2013). Due to the various components of this disease, it can be difficult to choose which interventions would be most beneficial for individuals with PD that are presenting with walking problems. The overall purpose of this research is to first explore the exercise habits of individuals with PD to understand what type of exercise is being utilized to combat this progressive neurodegenerative disorder that currently has no cure. It will aim to understand how intense individuals are perceiving their workouts and what barriers exist to PD symptom management. Neuroplastic fundamentals suggest that specificity of selected exercise, repetition of activities and intensity of work can all positively impact direct recovery after a neurological diagnosis. Furthermore, incorporating exercise at higher intensities has been established as an intervention to improve functional mobility for individuals with stroke, traumatic brain injury and spinal cord injury but little is known about its impact with the PD population. This research will build on the knowledge gained about current exercise habits and couple it with current best evidence to develop an intervention that targets improving clinically meaningful outcomes with goals to address the multifactorial components of PD

Calcium influx: is Homer the missing link?

AbstractCalcium signals in cells can arise via release from intracellular stores or influx across the plasma membrane. Recent studies have shed new light on the multi-protein signalling complexes that mediate communication between calcium stores and plasma membrane calcium channels

Recent Progress in the Regulation of TRPC1 by Store Depletion

Store-operated Ca entry (SOCE) is activated in response to depletion of the ER-Ca stores. The ER-Ca 2+ sensor protein, STIM1, oligomerizes when [Ca ] in the store is decreased and moves to ER/PM junctional domains where it interacts with and activates channels involved in SOCE, namely Orai and TRPC channels. 2+ Orai1 is the primary pore-forming component of the highly Ca selective CRAC channel. It is recruited to ER/ PM junctional domains by STIM1 where it is gated via interaction with a specific C-terminal domain of STIM1. Thus Orai1 and STIM1 are sufficient for generation of functional CRAC channels. Store depletion also leads to activation of relatively non-selective cation channels, referred to as SOC channels that contribute to SOCE in several other cell types. TRPC1 has been proposed as a possible candidate component of SOC channels. 2+ TRPC1 contributes to endogenous SOCE in many cells types. In these cells, TRPC1-mediated Ca entry and 3+ cation currents are stimulated with either agonist or thapsigargin, and inhibited by low [Gd ] and 10-20 µM 2APB (conditions that block SOCE). STIM1 also associates with and gates TRPC1 via electrostatic interaction between STIM1 (684KK685) and TRPC1 (639DD640). Further, functional Orai1 is required for activation of TRPC1-SOCE and this has been associated with recruitment of a TRPC1/STIM1/Orai1 complex. However, there is ongoing debate regarding the activation of TRPC1 by store depletion as well as the role of Orai1 and STIM1 in regulating its function. This chapter will summarize recent studies and concepts regarding the contri- butions of Orai1 and TRPC1 to SOCE. We will discuss major unresolved questions regarding functional inter- action between Orai1 and TRPC1 as well as possible mechanisms involved in the regulation of TRPC channels