Highly Flexible and Durable Thermoelectric Power Generator Using CNT/PDMS Foam by Rapid Solvent Evaporation.

Using a simple, rapid solvent evaporation process, the authors produced 3D carbon nanotube (CNT)/polydimethylsiloxane (PDMS) foams with both high thermoelectric (TE) and good mechanical performance and used them to fabricate highly flexible and durable TE generators. The numerous pores and interfaces in the CNT/PDMS foams, which have porosities exceeding 87%, afford very low thermal conductivity of 0.13 W m-1 K-1 . The foam has a zT value of 6.6 × 10-3 , which is twice as high as that of pristine CNT foam. Importantly, the CNT/PDMS foam exhibits good tensile strength of 0.78 MPa, elongation greater than 20%, and excellent resilience even at compressive strain of 80%. This foam is used to fabricate a highly flexible TE foam generator that exhibits a moderate output power of 1.9 µW generated from the large temperature gradient of 18.1 K produced by applied heat. The authors also demonstrate a practical TE foam generator that produces sustainable output power of 3.1 µW under a compressive strain of 80% and 38.2 nW under the continuous vibrational stress produced by a car engine. The TE foam generator also exhibits excellent stability and durability under cyclic bending and harsh vibrational stress.

Fe-P: a new class of electroactive catalyst for oxygen reduction reaction.

It has been long thought that Fe-N-C structure, where Fe is bonded with an electronegative heteroatom N, plays a key role as nonprecious metal catalyst for oxygen reduction reaction (ORR) in fuel cells. However, electrocatalytic activity of Fe bonded with electropositive heteroatom P has never been considered for ORR. Herein we report the electrocatalytic activity for ORR of new Fe-P-C.

The incidence, risk factors, and outcomes of acute kidney injury in patients with pyogenic liver abscesses.

BACKGROUND: Acute kidney injury (AKI) can occur in various infectious conditions. Liver abscess is relatively rare, but can lead to sepsis and/or other severe complications. Few studies of AKI in patients with a liver abscess have been conducted. Therefore, we analyzed the clinical and laboratory data of AKI in patients with a liver abscess. METHODS: We retrospectively reviewed the medical records of patients who were diagnosed with a liver abscess from January 2000 to March 2013. The study included 404 patients with a liver abscess confirmed by clinical presentation and computed tomography. RESULTS: AKI occurred in 137 patients (34 %). As per RIFLE classification, renal injury was graded as either at risk of renal dysfunction (35.8 %), renal injury (47.4 %), and renal failure (16.5 %). AKI occurred more frequently in males and patients with liver cirrhosis (P < 0.001 and P = 0.005). Patients with AKI had lower serum albumin and higher AST and ALT levels than did patients without AKI. Bacteria were frequently isolated in AKI patients from blood culture and liver abscess aspirates (P < 0.001 and P = 0.007). The occurrence of septic shock was positively correlated with AKI (P = 0.002) and AKI was more frequent in patients with chronic kidney disease (P = 0.04). Higher mortality was observed in CKD patients accompanied by AKI (P < 0.001). Three patients with AKI underwent hemodialysis; two patients who had initially normal renal function completely recovered whereas one CKD patient progressed to ESRD, requiring maintenance hemodialysis. CONCLUSION: AKI is relatively common in patients with liver abscess. Physicians should therefore attempt to prevent, detect, and manage AKI early in patients with liver abscess.

Hemolytic uremic syndrome associated with paraquat intoxication.

We report a case of a 66-year-old patient with paraquat intoxication resulting in the requirement for hemoperfusion, hemodialysis, and plasma exchange. His initial serum paraquat level was 0.24 µg/mL (0.0-0.1 µg/mL). Activated charcoal (50 g) was administered orally, and high-dose N-acetylcysteine (150 mg/kg) was administered intravenously. In addition, immediate 4 h hemoperfusion was also performed for three consecutive days after admission. Hemodialysis was started on the 4th day after admission because of uremia. On the 9th day after admission, laboratory findings demonstrated hemolytic uremic syndrome (HUS): microangiopathic hemolytic anemia (MAHA), thrombocytopenia, elevated reticulocyte count, and lactate dehydrogenase (LDH). Plasma exchange was performed three times consecutively. Anemia and thrombocytopenia were improved, and LDH was normalized after plasma exchange. Urine output increased to 2240 mL/day on the 18th day after admission, and hemodialysis was discontinued. He is currently being observed at our follow-up clinic without renal impairment or pulmonary dysfunction for 1.5 years since discharge. We should suspect paraquat-associated HUS when thrombocytopenia and anemia are maintained for a long time after paraquat intoxication.

Iodine-induced thyrotoxic hypokalemic paralysis after ingestion of Salicornia herbace.

A 56-year-old Korean man visited to emergency room due to paroxysmal flaccid paralysis in his lower extremities. There was no family or personal history of periodic paralysis. His initial potassium levels were 1.8 mmol/L. The patient had been taking Salicornia herbacea for the treatment of diabetes and hypertension. Results of a thyroid function test were as follows: T3 = 130.40 ng/dL, TSH = 0.06 mIU/L, and free T4 = 1.73 ng/dL. A thyroid scan exhibited a decreased uptake (0.6%). His symptoms clearly improved and serum potassium levels increased to 4.4 mmol/L by intravenous infusion of only 40 mmol of potassium chloride. Eight months after the discontinuation of only Salicornia herbacea, the patient's thyroid function tests were normalized. Large amounts of iodine can induce hypokalemic thyrotoxic paralysis and it may be necessary to inquire about the ingestion of iatrogenic iodine compounds, such as Salicornia herbacea.

A retrospective study of short- and long-term effects on renal function after acute renal infarction.

PURPOSE: Acute renal infarction is often missed or diagnosed late due to its rarity and non-specific clinical manifestations. This study analyzed the clinical and laboratory findings of patients diagnosed with renal infarction to determine whether it affects short- or long-term renal prognosis. METHODS: We retrospectively reviewed the medical records of 100 patients diagnosed as acute renal infarction from January 1995 to September 2012 at Gyeongsang National University Hospital, Jinju, South Korea. RESULTS: Acute kidney injury (AKI) occurred in 30 patients. Infarct size was positively correlated with the occurrence of AKI (p = 0.004). Compared with non-AKI patients, AKI occurrence was significantly correlated with degree of proteinuria (p < 0.001) and the presence of microscopic hematuria (p = 0.035). AKI patients had higher levels of aspartate transaminase (p < 0.001), alanine transaminase (p < 0.001), and lactated dehydrogenase (p = 0.027). AKI after acute renal infarction was more common in patients with chronic renal failure (CRF) (eGFR < 60 mL/min), compared with non-CRF patients, whose baseline eGFR was >60 mL/min (p = 0.003). Most patients recovered from AKI, except for seven patients (7%) who developed persistent renal impairment (chronic kidney disease progression) closely correlated with magnitude of infarct size (p = 0.015). Six AKI patients died due to combined comorbidity. CONCLUSIONS: AKI is often associated with acute renal infarction. Although most AKI recovers spontaneously, renal impairment following acute renal infarction can persist. Thus, early diagnosis and intervention are needed to preserve renal function.

CRISPR-based identification of N-terminal acetylation in synucleinopathies.

A recent study by Kumar et al. identified several biological pathways that regulate the levels of endogenous alpha-synuclein (α-synuclein). They specifically highlighted the N-terminal acetylation (NTA) pathway as an important factor in maintaining the stability of endogenous α-synuclein, suggesting targeting the NTA pathway as a potential therapeutic approach.

Targeted degradation of SNCA/α-synuclein aggregates in neurodegeneration using the AUTOTAC chemical platform.

Parkinson disease (PD) characterized by dopaminergic neuronal loss is caused by aggregation of misfolded SNCA/α-synuclein. We recently developed autophagy-targeting chimera (AUTOTAC), a targeted protein degradation (TPD) technology based on the macroautophagy/autophagy-lysosome pathway (ALP). In this study, we employed AUTOTAC to synthesize ATC161, a chimeric compound that adopts Anle138b as target-binding ligand (TBL) for SNCA aggregates. The autophagy-targeting ligand (ATL) of ATC161 was designed to allosterically activate the autophagy receptor SQSTSM1/p62 (sequestosome 1), a key step for targeting SNCA aggregates to the phagophore. The lysosomal degradation of SNCA aggregates by ATC161 acutely occurs at DC50 of 100-500 nM with no significant off-target degradation of monomeric SNCA. ATC161 protects cells from DNA and mitochondrial damage by SNCA aggregates. In PD model mice, oral administration of ATC161 decreases the level of SNCA aggregates and their propagation across brain regions, which mitigates glial inflammatory responses and improves muscle strength and locomotive activity. An Investigational New Drug (IND) was approved by the Korean Food and Drug Administration for a phase 1 clinical trial to treat PD, Alzheimer disease (AD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS). We suggest that AUTOTAC provides a platform for drug discovery in proteinopathies and other diseases.

Antibody-aided clearance of extracellular α-synuclein prevents cell-to-cell aggregate transmission.

Abnormal deposition and intercellular propagation of α-synuclein plays a central role in the pathogenesis of disorders such as Parkinson's Disease (PD) and dementia with Lewy bodies (DLB). Previous studies demonstrated that immunization against α-synuclein resulted in reduced α-synuclein accumulation and synaptic loss in a transgenic (tg) mouse model, highlighting the potential for immunotherapy. However, the mechanism by which immunization prevents synucleinopathy-associated deficits remains unknown. Here, we show that antibodies against α-synuclein specifically target and aid in clearance of extracellular α-synuclein proteins by microglia, thereby preventing their actions on neighboring cells. Antibody-assisted clearance occurs mainly in microglia through the Fcγ receptor, and not in neuronal cells or astrocytes. Stereotaxic administration of antibody into the brains of α-synuclein tg mice prevented neuron-to-astroglia transmission of α-synuclein and led to increased localization of α-synuclein and the antibody in microglia. Furthermore, passive immunization with α-synuclein antibody reduced neuronal and glial accumulation of α-synuclein and ameliorated neurodegeneration and behavioral deficits associated with α-synuclein overexpression. These findings provide an underlying mechanistic basis for immunotherapy for PD/DLB and suggest extracellular forms of α-synuclein as potential therapeutic targets.

Changes in oligodendroglial subpopulations in Parkinson's disease.

Parkinson's disease (PD) is characterized by a selective loss of dopaminergic neurons. While most research on PD conducted to date has focused on neurons and, to a certain extent, glia, few studies have investigated changes in oligodendroglia. Here, we investigated the heterogeneity of oligodendrocytes from PD patients compared with those of control cases by analyzing single-nuclei transcriptomes. These analyses revealed the presence of distinct oligodendrocyte populations in PD patients indicative of corresponding variations in molecular features, notably including activation of inflammatory responses, response to protein folding stress, and myelination abnormalities. We confirmed myelination abnormalities in an α-synuclein preformed fibril-injection mouse model of PD. These results suggest that oligodendrocytes acquire disease-associated phenotypes in PD and may contribute to the accompanying neurodegeneration.

Estimating the Total Societal Cost of a Hexavalent Vaccine versus a Pentavalent Vaccine with Hepatitis B in South Korea.

In South Korea, the ready-to-use hexavalent vaccine (against diphtheria, tetanus, pertussis, poliovirus, Haemophilus influenzae type b, and hepatitis B) is not listed despite its facility of no need to reconstitute. It, therefore, has the potential to augment the efficiency of prevention against the six infectious diseases, and it may reduce vaccine-related errors of reconstitution when compared with the currently used vaccination scheme of the pentavalent vaccine with the additional shots against hepatitis B. Given the assumed clinical equivalence between the two vaccination schemes, a cost-minimization analysis has been performed from a societal perspective including all the medical and non-medical direct and indirect costs when vaccinating one birth cohort. The results indicate that the ready-to-use hexavalent vaccine induces a cost reduction of KRW 47,155 (USD36.22) per infant or 12,026 million Korean Won ($9,236,417) in total for the whole birth cohort with 260,500 children. Using the ready-to-use hexavalent vaccine causes a lower infection rate, has fewer vaccination sessions, and may save much time as compared with the current vaccination scheme in place. The ready-to-use hexavalent vaccine may, therefore, benefit the National Immunization Program by reducing the total societal costs of vaccination while improving convenience of infants, parents, and medical care professionals.

Targeted degradation of ⍺-synuclein aggregates in Parkinson's disease using the AUTOTAC technology.

BACKGROUND: There are currently no disease-modifying therapeutics for Parkinson's disease (PD). Although extensive efforts were undertaken to develop therapeutic approaches to delay the symptoms of PD, untreated α-synuclein (α-syn) aggregates cause cellular toxicity and stimulate further disease progression. PROTAC (Proteolysis-Targeting Chimera) has drawn attention as a therapeutic modality to target α-syn. However, no PROTACs have yet shown to selectively degrade α-syn aggregates mainly owing to the limited capacity of the proteasome to degrade aggregates, necessitating the development of novel approaches to fundamentally eliminate α-syn aggregates. METHODS: We employed AUTOTAC (Autophagy-Targeting Chimera), a macroautophagy-based targeted protein degradation (TPD) platform developed in our earlier studies. A series of AUTOTAC chemicals was synthesized as chimeras that bind both α-syn aggregates and p62/SQSTM1/Sequestosome-1, an autophagic receptor. The efficacy of Autotacs was evaluated to target α-syn aggregates to phagophores and subsequently lysosomes for hydrolysis via p62-dependent macroautophagy. The target engagement was monitored by oligomerization and localization of p62 and autophagic markers. The therapeutic efficacy to rescue PD symptoms was characterized in cultured cells and mice. The PK/PD (pharmacokinetics/pharmacodynamics) profiles were investigated to develop an oral drug for PD. RESULTS: ATC161 induced selective degradation of α-syn aggregates at DC50 of ~ 100 nM. No apparent degradation was observed with monomeric α-syn. ATC161 mediated the targeting of α-syn aggregates to p62 by binding the ZZ domain and accelerating p62 self-polymerization. These p62-cargo complexes were delivered to autophagic membranes for lysosomal degradation. In PD cellular models, ATC161 exhibited therapeutic efficacy to reduce cell-to-cell transmission of α-syn and to rescue cells from the damages in DNA and mitochondria. In PD mice established by injecting α-syn preformed fibrils (PFFs) into brain striata via stereotaxic surgery, oral administration of ATC161 at 10 mg/kg induced the degradation of α-syn aggregates and reduced their propagation. ATC161 also mitigated the associated glial inflammatory response and improved muscle strength and locomotive activity. CONCLUSION: AUTOTAC provides a platform to develop drugs for PD. ATC161, an oral drug with excellent PK/PD profiles, induces selective degradation of α-syn aggregates in vitro and in vivo. We suggest that ATC161 is a disease-modifying drug that degrades the pathogenic cause of PD.

Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein.

Neuronal accumulation of alpha-synuclein and Lewy body formation are characteristic to many neurodegenerative diseases, including Parkinson's disease (PD). This Lewy pathology appears to spread throughout the brain as the disease progresses. Furthermore, recent studies showed the occurrence of Lewy pathology in neurons grafted into the brains of PD patients, suggesting the spread of pathology from the host tissues to the grafts. The mechanism underlying this propagation is unknown. Here, we show that alpha-synuclein is transmitted via endocytosis to neighboring neurons and neuronal precursor cells, forming Lewy-like inclusions. Moreover, alpha-synuclein was transmitted from the affected neurons to engrafted neuronal precursor cells in a transgenic model of PD-like pathology. Failure of the protein quality control systems, especially lysosomes, promoted the accumulation of transmitted alpha-synuclein and inclusion formation. Cells exposed to neuron-derived alpha-synuclein showed signs of apoptosis, such as nuclear fragmentation and caspase 3 activation, both in vitro and in vivo. These findings demonstrate the cell-to-cell transmission of alpha-synuclein aggregates and provide critical insights into the mechanism of pathological progression in PD and other proteinopathies.

Anuric acute renal failure associated with pericardial effusion without signs of cardiac tamponade.

This article describes the anuric acute renal failure (ARF) secondary to massive pericardial effusion without tamponade in an 84 year-old man. He was referred to our emergency room with progressive dyspnea and azotemia. An electrocardiogram showed sinus tachycardia. A two-dimensional echocardiogram confirmed the presence of severe pericardial effusion without prominent ventricular diastolic collapse and there were no changes in his vital signs. Laboratory findings showed that his blood urea nitrogen and serum creatinine levels were 91.8 and 3.77 mg/dL, respectively. Renal ultrasonography showed no signs of hydronephrosis. Urine output did not increase in spite of giving a saline and furosemide infusion but increased immediately after pericardiocentesis with drainage. His renal function was completely restored 3 days after the procedure. A pericardial biopsy demonstrated invasion of malignant cells. We should keep in mind that pericardial effusion is one of the causes of anuric ARF, although it is not accompanied by tamponade.

Obstructive uropathy by total uterine prolapse leading to end-stage renal disease.

A 74-year-old woman was admitted to our emergency room complaining of general weakness and anorexia that started 20 days earlier. She denied other underlying diseases that might have provoked chronic renal disease. Her serum creatinine was 12.35 mg/dL. A pelvic examination and computed tomography revealed severe bilateral hydroureteronephrosis with marked cortical thinning induced by total uterine prolapse. She was started on emergency hemodialysis due to her uremic symptoms and severe metabolic acidosis. Despite Foley catheter insertion and manual reduction of uterus for 1 month, renal function was not recovered. The department of gynecology was strongly opposed to performing a procedure to reverse the hydroureteronephrosis due to the irreversibility of her renal function. She is undergoing chronic maintenance hemodialysis. This is a case report of rare end-stage renal disease (ESRD) caused by obstructive uropathy due to pelvic organ prolapse (POP). We should consider POP as a cause of ESRD.

TNF-α promotes α-synuclein propagation through stimulation of senescence-associated lysosomal exocytosis.

Cell-to-cell propagation of α-synuclein is thought to be the underlying mechanism of Parkinson's disease progression. Recent evidence suggests that inflammation plays an important role in the propagation of protein aggregates. However, the mechanism by which inflammation regulates the propagation of aggregates remains unknown. Here, using in vitro cultures, we found that soluble factors secreted from activated microglia promote cell-to-cell propagation of α-synuclein and further showed that among these soluble factors, TNF-α had the most robust stimulatory activity. Treatment of neurons with TNF-α triggered cellular senescence, as shown by transcriptomic analyses demonstrating induction of senescence-associated genes and immunoanalysis of senescence phenotype marker proteins. Interestingly, secretion of α-synuclein was increased in senescent neurons, reflecting acquisition of a senescence-associated secretory phenotype (SASP). Using vacuolin-1, an inhibitor of lysosomal exocytosis, and RNAi against rab27a, we demonstrated that the SASP was mediated by lysosomal exocytosis. Correlative light and electron microscopy and immunoelectron microscopy confirmed that propagating α-synuclein aggregates were present in electron-dense lysosome-like compartments. TNF-α promoted the SASP through stimulation of lysosomal exocytosis, thereby increasing the secretion of α-synuclein. Collectively, these results suggest that TNF-α is the major inflammatory factor that drives cell-to-cell propagation of α-synuclein by promoting the SASP and subsequent secretion of α-synuclein.

Inflammation promotes synucleinopathy propagation.

The clinical progression of neurodegenerative diseases correlates with the spread of proteinopathy in the brain. The current understanding of the mechanism of proteinopathy spread is far from complete. Here, we propose that inflammation is fundamental to proteinopathy spread. A sequence variant of α-synuclein (V40G) was much less capable of fibril formation than wild-type α-synuclein (WT-syn) and, when mixed with WT-syn, interfered with its fibrillation. However, when V40G was injected intracerebrally into mice, it induced aggregate spreading even more effectively than WT-syn. Aggregate spreading was preceded by sustained microgliosis and inflammatory responses, which were more robust with V40G than with WT-syn. Oral administration of an anti-inflammatory agent suppressed aggregate spreading, inflammation, and behavioral deficits in mice. Furthermore, exposure of cells to inflammatory cytokines increased the cell-to-cell propagation of α-synuclein. These results suggest that the inflammatory microenvironment is the major driver of the spread of synucleinopathy in the brain.

Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies.

Abnormal neuronal aggregation of alpha-synuclein is implicated in the development of many neurological disorders, including Parkinson disease and dementia with Lewy bodies. Glial cells also show extensive alpha-synuclein pathology and may contribute to disease progression. However, the mechanism that produces the glial alpha-synuclein pathology and the interaction between neurons and glia in the disease-inflicted microenvironment remain unknown. Here, we show that alpha-synuclein proteins released from neuronal cells are taken up by astrocytes through endocytosis and form inclusion bodies. The glial accumulation of alpha-synuclein through the transmission of the neuronal protein was also demonstrated in a transgenic mouse model expressing human alpha-synuclein. Furthermore, astrocytes that were exposed to neuronal alpha-synuclein underwent changes in the gene expression profile reflecting an inflammatory response. Induction of pro-inflammatory cytokines and chemokines correlated with the extent of glial accumulation of alpha-synuclein. Together, these results suggest that astroglial alpha-synuclein pathology is produced by direct transmission of neuronal alpha-synuclein aggregates, causing inflammatory responses. This transmission step is thus an important mediator of pathogenic glial responses and could qualify as a new therapeutic target.

Incidence and risk factors for radiocontrast-induced nephropathy in patients with hepatocellular carcinoma undergoing transcatheter arterial chemoembolization.

BACKGROUND: Transcatheter arterial chemoembolization (TACE) is an effective treatment for unresectable hepatocellular carcinoma (HCC); however, large volumes of radiocontrast agents are used for TACE and may induce renal dysfunction. Most patients with HCC have coexisting liver cirrhosis (LC) at the time of diagnosis. Advanced cirrhosis is characterized by peripheral vasodilatation associated with decreased renal perfusion due to the activation of vasoconstrictor systems. We retrospectively investigated patients with HCC who had undergone TACE to determine the incidence and risk factors for radiocontrast-induced nephropathy (RCIN). METHODS: A total of 101 patients with HCC who underwent a combined 221 TACE treatment sessions were included. Follow-up serum creatinine levels within 96 h after TACE were confirmed in these patients. RCIN was defined as an increase of at least 25% in baseline serum creatinine levels between 48 and 96 h after TACE. RESULTS: RCIN developed in 20 (9%) of the 221 treatment sessions after TACE. A univariate analysis showed that the Child-Pugh score (6.0 ± 1.3 vs. 6.7 ± 1.9, P = 0.005), ascites (14.4 vs. 40%, P = 0.008), contrast medium volume (257.3 ± 66.8 vs. 275.0 ± 44.0 ml, P = 0.009), total bilirubin (1.3 ± 1.7 vs. 3.4 ± 8.0 mg/dl, P < 0.001), basal serum creatinine levels (0.9 ± 0.3 vs. 1.0 ± 0.5 mg/dl, P < 0.001) and glomerular filtration rate using the modification of diet in renal disease formula (90.5 ± 21.8 vs. 88.4 ± 29.6 ml/min, P = 0.015) were significantly associated with the development of RCIN. A multivariate analysis revealed that the Child-Pugh score was associated with RCIN [odds ratio (OR) 1.5; P = 0.015]. Overall, in-hospital mortality after TACE was 4.07% (with RCIN, 30%; without RCIN, 1.5%; P < 0.001). The multivariate analysis also showed that the Child-Pugh score and the occurrence of RCIN were associated with in-hospital mortality after TACE (OR 2.8; P = 0.001; OR 26.7, P = 0.002, respectively). CONCLUSIONS: RCIN after TACE was closely associated with the severity of LC. Effective preventive measures remain to be determined in patients with HCC and advanced LC who are undergoing TACE.

Neurodevelopmental defects and neurodegenerative phenotypes in human brain organoids carrying Parkinson's disease-linked DNAJC6 mutations.

Loss-of-function mutations of DNAJC6, encoding HSP40 auxilin, have recently been identified in patients with early-onset Parkinson's disease (PD). To study the roles of DNAJC6 in PD pathogenesis, we used human embryonic stem cells with CRISPR-Cas9-mediated gene editing. Here, we show that DNAJC6 mutations cause key PD pathologic features, i.e., midbrain-type dopamine (mDA) neuron degeneration, pathologic α-synuclein aggregation, increase of intrinsic neuronal firing frequency, and mitochondrial and lysosomal dysfunctions in human midbrain-like organoids (hMLOs). In addition, neurodevelopmental defects were also manifested in hMLOs carrying the mutations. Transcriptomic analyses followed by experimental validation revealed that defects in DNAJC6-mediated endocytosis impair the WNT-LMX1A signal during the mDA neuron development. Furthermore, reduced LMX1A expression during development caused the generation of vulnerable mDA neurons with the pathologic manifestations. These results suggest that the human model of DNAJC6-PD recapitulates disease phenotypes and reveals mechanisms underlying disease pathology, providing a platform for assessing therapeutic interventions.