Inferior Olivary nucleus degeneration does not lessen tremor in essential tremor

Background In traditional models of essential tremor, the inferior olivary nucleus was posited to play a central role as the pacemaker for the tremor. However, recent data call this disease model into question. Case presentation Our patient had progressive, long-standing, familial essential tremor. Upper limb tremor began at age 10 and worsened over time. It continued to worsen during the nine-year period he was enrolled in our brain donation program (age 85 – 94 years), during which time the tremor moved from the moderate to severe range on examination. On postmortem examination at age 94, there were degenerative changes in the cerebellar cortex, as have been described in the essential tremor literature. Additionally, there was marked degeneration of the inferior olivary nucleus, which was presumed to be of more recent onset. Such degeneration has not been previously described in essential tremor postmortems. Despite the presence of this degeneration, the patient’s tremor not only persisted but it continued to worsen during the final decade of his life. Conclusions Although the pathophysiology of essential tremor is not completely understood, evidence such as this suggests that the inferior olivary nucleus does not play a critical role in the generation of tremor in these patients

Endoplasmic reticulum-plasma membrane contact sites integrate sterol and phospholipid regulation

Tether proteins attach the endoplasmic reticulum (ER) to other cellular membranes, thereby creating contact sites that are proposed to form platforms for regulating lipid homeostasis and facilitating non-vesicular lipid exchange. Sterols are synthesized in the ER and transported by non-vesicular mechanisms to the plasma membrane (PM), where they represent almost half of all PM lipids and contribute critically to the barrier function of the PM. To determine whether contact sites are important for both sterol exchange between the ER and PM and intermembrane regulation of lipid metabolism, we generated Δ-super-tether (Δ-s-tether) yeast cells that lack six previously identified tethering proteins (yeast extended synatotagmin [E-Syt], vesicle-associated membrane protein [VAMP]-associated protein [VAP], and TMEM16-anoctamin homologues) as well as the presumptive tether Ice2. Despite the lack of ER-PM contacts in these cells, ER-PM sterol exchange is robust, indicating that the sterol transport machinery is either absent from or not uniquely located at contact sites. Unexpectedly, we found that the transport of exogenously supplied sterol to the ER occurs more slowly in Δ-s-tether cells than in wild-type (WT) cells. We pinpointed this defect to changes in sterol organization and transbilayer movement within the PM bilayer caused by phospholipid dysregulation, evinced by changes in the abundance and organization of PM lipids. Indeed, deletion of either OSH4, which encodes a sterol/phosphatidylinositol-4-phosphate (PI4P) exchange protein, or SAC1, which encodes a PI4P phosphatase, caused synthetic lethality in Δ-s-tether cells due to disruptions in redundant PI4P and phospholipid regulatory pathways. The growth defect of Δ-s-tether cells was rescued with an artificial "ER-PM staple," a tether assembled from unrelated non-yeast protein domains, indicating that endogenous tether proteins have nonspecific bridging functions. Finally, we discovered that sterols play a role in regulating ER-PM contact site formation. In sterol-depleted cells, levels of the yeast E-Syt tether Tcb3 were induced and ER-PM contact increased dramatically. These results support a model in which ER-PM contact sites provide a nexus for coordinating the complex interrelationship between sterols, sphingolipids, and phospholipids that maintain PM composition and integrity

Inferior Olivary nucleus degeneration does not lessen tremor in essential tremor

Background In traditional models of essential tremor, the inferior olivary nucleus was posited to play a central role as the pacemaker for the tremor. However, recent data call this disease model into question. Case presentation Our patient had progressive, long-standing, familial essential tremor. Upper limb tremor began at age 10 and worsened over time. It continued to worsen during the nine-year period he was enrolled in our brain donation program (age 85 – 94 years), during which time the tremor moved from the moderate to severe range on examination. On postmortem examination at age 94, there were degenerative changes in the cerebellar cortex, as have been described in the essential tremor literature. Additionally, there was marked degeneration of the inferior olivary nucleus, which was presumed to be of more recent onset. Such degeneration has not been previously described in essential tremor postmortems. Despite the presence of this degeneration, the patient’s tremor not only persisted but it continued to worsen during the final decade of his life. Conclusions Although the pathophysiology of essential tremor is not completely understood, evidence such as this suggests that the inferior olivary nucleus does not play a critical role in the generation of tremor in these patients